Development of the Nervous System

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Chapter 3 Development of the Nervous System

The entire nervous system and the special sense organs originate from three sources, each derived from specific cell populations of the early epiblast termed neural ectoderm. The first source to be clearly delineated is the neural plate, which gives rise to the central nervous system (CNS), the somatic motor nerves and the preganglionic autonomic nerves. The second source is from cells at the perimeter of the neural plate, which remove themselves by epithelial–mesenchymal transition from the plate just prior to its fusion as a neural tube. These are the neural crest cells, and they form nearly all the peripheral nervous system (PNS), including the somatic sensory nerves, somatic and autonomic ganglia, postganglionic autonomic nerves and adrenal and chromaffin cells. They also give rise to significant mesenchymal populations in the head. The third source is from ectodermal placodes, a group of cells that originate at the edge of the neural plate but remain in the surface ectoderm after neural tube formation, undergoing epithelial–mesenchymal transformation after the neural crest cells have started their migration. Ectodermal placodes contribute to the cranial sensory ganglia, the hypophysis, the inner ear and, by a non-neuronal contribution, the lens of the eye.

With the initiation of gastrulation, the first populations of epiblast cells to invaginate through the primitive streak form the prechordal plate, embryonic endoderm and notochord. These cells invaginate through the rostral end of the primitive streak (Hensen’s node in the chick). The node gives rise concomitantly to the midline floor plate of the neural plate, which extends with the subjacent notochord to the buccopharyngeal membrane. The neural plate is a thickened epithelium; it is roughly oval, but wider rostrally and narrower caudally. It extends over the paraxial mesenchyme invaginating from the more caudal regions of the primitive streak.

Neurulation

Primary neurulation begins at stage 9 (Fig. 3.1). Although the process is continuous spatially and temporally, it has been envisaged as four stages. It begins with local elongation of the ectoderm cells in a midline zone of the disc and their reorganization into a pseudostratified epithelium, the neural plate. This is followed by reshaping of the neural plate and bending of the plate into a neural groove. The latter is closed to form a neural tube bidirectionally from the midportion to its cranial and caudal ends. A continuous surface ectoderm forms dorsal to the tube.

The regions of rostral and caudal fusion are termed rostral and caudal neuropores, respectively. However, there may be more than one region of fusion. Primary neurulation occurs contemporaneously with somitogenesis; its success depends on the cellular changes and movements of the paraxial mesenchyme. The neural ectodermal cells become elongated and then wedge shaped. It has been suggested that the forces needed to shape the neural tube are intrinsic to the cells of the neuroectoderm. When the neural tube is closing, its walls consist of a single layer of columnar neural epithelial cells whose extremities abut on internal and external limiting membranes. The columnar cells increase in length and develop numerous longitudinally disposed microtubules. The borders of their luminal ends are firmly attached to adjacent cells by junctional complexes, and the cytoplasmic aspect of the complexes are associated with a dense paraluminal web of microfilaments. The nuclei assume basal positions; this, together with the disposition of organelles, imparts a slight wedge conformation on some of the cells and creates a hinge point.

The position of hinge points within the neural plate determines the characteristics of the formed neural tube. With a median hinge point, the neural folds remain relatively straight, and the tube in this position has a slit-shaped lumen; this can be seen from the initial region of fusion rostralward. If dorsolateral hinge points are added, the resulting neural tube is rhombic, as can be seen from the initial region of fusion caudally. If all the neuroepithelial cells exhibit some apical narrowing, the resulting tube has a circular lumen. The rostral slit-shaped profile of the neural tube may depend more on support from adjacent tissues than does the caudal end of the tube, where neurulation is generated by the neuroepithelium. The transition from primary to secondary neurulation continues the production of a neural tube with a circular lumen.

Secondary neurulation is a process that has only recently undergone more extensive study. Primary neurulation ceases when the neural tube has closed completely; the rostral neuropore closes during stage 11 (24 days), and the caudal neuropore closes during stage 12. There is some discrepancy in the literature about the level of the caudal neuropore at the start and end of closure. It is expressed as a somite level, ranging from somite 25 to somite 31. The level is significant because the junction of primary and secondary neurulation can be a site of future anomalies of neural development. Somite 27 participates in the formation of thoracic vertebra 12 and lumbar vertebra 1, and somite 31 corresponds to sacral vertebra 2. When the caudal neuropore reaches a certain level, the cell populations for these caudal somites have already been produced from the unsegmented paraxial mesenchyme, which compounds the difficulty of specifying the level.

At the time of caudal neuropore closure the midline cells located caudally are generically termed the tail bud. A specific population called the caudoneural hinge shares the same molecular markers as the primitive node. These cells aggregate at the midline and undergo mesenchymal–epithelial transformation, which produces a cellular cylinder contiguous with the caudal end of the neural tube. Further elongation of the caudal neural tube involves cavitation of the neural cylinder. Neural crest cells delaminate from the dorsal surface of the cylinder in a rostrocaudal direction. Concurrently, the paraxial mesenchyme undergoes somitogenesis.

The main difference between primary and secondary neurulation is that the latter leads to the formation of a neural tube in the absence of a neural plate. Close to the level of the caudal neuropore, these processes overlap both temporally and spatially.

Early Vesicles and Flexures of the Neural Tube

Prior to closure of the neural tube, the neural folds become considerably expanded in the head region—the first indication of a brain. After the rostral neuropore closes, these regional expansions form three primary cerebral vesicles (Fig. 3.2). The term ‘vesicle’ may be a misnomer, because it suggests an exaggerated view of these localized accelerations of growth in the wall of the brain. The bulging is not initially marked, and the vesicles are more like gently fusiform tubes. The three regions are the prosencephalon (forebrain), mesencephalon (midbrain) and rhombencephalon (hindbrain), the last being continuous caudally with the spinal cord. As a result of unequal growth of their different regions, the prosencephalon and rhombencephalon enlarge more than the mesencephalon and can be subdivided. The prosencephalon gives rise to a midline diencephalon and bilateral telencephalon; the rhombencephalon gives rise to the metencephalon and myelencephalon. A summary of the derivatives of the cerebral vesicles is given in Table 3.1.

Table 3.1 Derivatives of the cerebral vesicles from caudal to rostral

Rhombencephalon (or hindbrain)
1. Myelencephalon Medulla oblongata
Caudal part of the fourth ventricle
Inferior cerebellar peduncles
2. Metencephalon Pons
Cerebellum
Middle part of the fourth ventricle
Middle cerebellar peduncles
3. Isthmus rhombencephali Superior medullary velum
Superior cerebellar peduncles
Rostral part of the fourth ventricle
Mesencephalon (or midbrain) Cerebral peduncles
Tegmentum
Tectum
Aqueduct
Prosencephalon (or forebrain)
1. Diencephalon Thalamus
Metathalamus
Subthalamus
Epithalamus
Caudal part of the hypothalamus
Caudal part of the third ventricle
2. Telencephalon Rostral part of the hypothalamus
Rostral part of the third ventricle
Cerebral hemispheres
Lateral ventricles
Cortex (archaeocortex, palaeocortex, neocortex)
Corpus striatum

Elongation of the brain occurs at the same time as the appearance of three flexures that are also developing prior to closure of the neural tube; two are concave ventrally, and one is concave dorsally. During stages 13 and 14 the brain bends at the mesencephalon (mesencephalic flexure), so the prosencephalon bends in a ventral direction around the cephalic end of the notochord and foregut until its floor lies almost parallel to that of the rhombencephalon (see Fig. 3.2). A bend also appears at the junction of the rhombencephalon and spinal cord (cervical flexure). This increases from the fifth to the end of the seventh week, by which time the rhombencephalon forms nearly a right angle to the spinal cord. However, after the seventh week, extension of the head takes place, and the cervical flexure diminishes and eventually disappears. The third bend, the pontine flexure, is directed ventrally between the metencephalon and myelencephalon. It does not substantially affect the outline of the head. In this region the roof plate thins until it is composed of only a single layer of cells and pia mater, the tela choroidea. The flexure of the neural tube at this point produces a rhombic shape in the roof that later forms the medullary velum.

In addition to these gross divisions, a number of ridges and depressions are present transiently on the inner surface of the brain. Prominent among these are the serial bulges that appear very early in the rhombencephalon, before the main flexures of the neural tube develop (Fig. 3.3). These bulges are termed rhombomeres.

Early Cellular Arrangement of the Neural Tube

Histologically, the early neural tube is composed of a pseudostratified neuroepithelium. It extends from the inner aspect of the tube to the outer limiting basal lamina and surrounding neural crest, which will form the pia mater. The epithelium contains stem cells that will give rise to populations of neuroblasts and glioblasts. A population of radial glia differentiates very early and provides a scaffold for later cells to follow. As development proceeds, three zones or layers develop (Figs. 3.43.6): an internal ventricular zone (variously termed the germinal, primitive ependymal or matrix layer), in which mitosis occurs and that contains the nucleated parts of the columnar cells and rounded cells undergoing mitosis; a middle mantle zone (also termed the intermediate zone), which contains the migrant cells from the divisions occurring in the ventricular zone; and an outer marginal zone, which initially consists of the external cytoplasmic processes of the radial glia and the neuroepithelial stem cells. The last is soon invaded by tracts of axonal processes that grow from neuroblasts developing in the mantle zone, together with varieties of non-neuronal cells (glial cells and later vascular endothelium and perivascular mesenchyme).

At first the neural tube caudal to the brain is oval in transverse section, and its lumen is narrow and slit-like (see Fig. 3.4). The original floor plate and the dorsal site of fusion of the tube initially contain non-neural cells. With cellular proliferation, the lateral walls thicken and the lumen, now the central canal, widens in its dorsal part and is somewhat diamond shaped on cross-section (see Fig. 3.6). Widening of the canal is associated with the development of a longitudinal sulcus limitans on each side. This divides the ventricular and mantle (intermediate) zones in each lateral wall into a ventrolateral lamina or basal plate and a dorsolateral lamina or alar plate. This separation indicates a fundamental functional difference.

Throughout the neural tube there is a generic pattern in the position of the neurones, specified by the juxtaposition of the notochord to the neural tube. Lateral or dorsal grafting of a notochord results in the induction of a floor plate overlying the grafted notochord and the induction of ectopic dorsal motor neurones. Similarly, lateral or dorsal grafts of a floor plate also result in the induction of a new floor plate overlying the graft and the induction of ectopic dorsal motor neurones. Removal of the notochord results in the elimination of the floor plate and motor neurones and the differentiation of dorsal cell types in the ventral region of the cord (Fig. 3.7).

image

Fig. 3.7 A–D, Successive stages in the development of the neural tube and spinal cord. A, The neural plate consists of epithelial cells. Cells in the midline of the neural plate are contacted directly by the notochord. More lateral regions of the neural plate overlie the paraxial mesenchyme (not shown). B, During neurulation, the neural plate bends at its midline, which elevates the lateral edges of the plate as the neural folds. Contact between the midline of the neural plate and the notochord is maintained at this stage. C, The neural tube is formed when the dorsal tips of the neural folds fuse. Cells in the region of fusion form the roof plate, which is a specialized group of dorsal midline cells. D, Cells at the ventral midline of the neural tube retain proximity to the notochord and differentiate into the floor plate. After neural tube closure, neuroepithelial cells continue to proliferate and eventually differentiate into defined classes of neurones at different dorsoventral positions within the spinal cord. For example, sensory relay, commissural and other classes of dorsal neurones (D) differentiate near the roof plate (R), and motor neurones (M) differentiate ventrally near the floor plate (F), which by this time is no longer in contact with the notochord (N). E–H, Summary of the results of experiments in chick embryos in which the notochord or floor plate is grafted to the dorsal midline of the neural tube or the notochord is removed before neural tube closure. E, The normal condition, showing the ventral location of motor neurones (M) and the dorsal location of sensory relay neurones (D). F, Dorsal grafts of a notochord result in induction of a floor plate in the dorsal midline and ectopic dorsal motor neurones (M). G, Dorsal grafts of a floor plate induce a new floor plate in the dorsal midline and ectopic dorsal motor neurones (M). H, Removal of the notochord results in the elimination of the floor plate and motor neurones and the expression of dorsal cells types (D) in the ventral region of the spinal cord.

(After Jessell, Dodd. 1992. WB Saunders.)

The basal plate is normally concerned predominantly with motor function and contains the cell bodies of motor neurones of the future anterior and lateral grey columns. The alar plate receives sensory inflow from external dorsal root ganglia. Motor and sensory axons combine to form the mixed nerves.

Neural Crest

The neuronal populations of the early epiblast are arranged in the medial region of the embryonic disc as the neural plate. Laterally, neural folds or crests indicate the transitional region between neural and surface ectoderm. Along most of the neuraxis the cells at the tips of the neural folds undergo an epithelial–mesenchymal transformation. They acquire migratory properties and leave the epithelium just prior to its fusion with the contralateral fold in the dorsal midline. The migratory cells so formed are collectively termed the neural crest (Brown, Keynes and Lumsden 2001). Cells within the rostral prosencephalic neural fold and smaller populations of cells in bilateral sites along the early brain do not form migratory neural crest cells but remain within the surface epithelium as ectodermal placodes.

Neural crest populations arise from the neural folds as primary neurulation proceeds and simultaneously progress rostrally and caudally. Crest cells migrate from the neural folds of the brain prior to tube closure. Caudally, from somite 27, secondary neurulation processes produce the most caudal neural crest. Two distinct populations of neural crest cells are formed: a neuronal population produced throughout the brain and spinal cord that gives rise to sensory and autonomic neurones and glia, and a non-neuronal mesenchymal population that arises only from the brain (Figs. 3.10, 3.11). Melanocytes develop from a subpopulation of neural crest cells derived from both the head and the trunk. They form one of the three pigment cell types (the others being retinal pigment epithelium and pigment cells of the pineal organ, both of which originate from the diencephalon).

In the trunk the migration patterns of neural crest cells are channelled by the somites. As the crest cells move laterally and ventrally they can pass between the somites and within the rostral sclerotomal half of each somite, but they cannot penetrate the caudal moiety of the sclerotomal mesenchyme. Thus the segmental distribution of the spinal and sympathetic ganglia is imposed on the neural crest cells by a prepattern that exists within the somitic paraxial mesenchyme (Fig. 3.12).

Rostral to the otic vesicle, neural crest cells arise from specific regions of the brain. Within the rhombencephalon a number of transverse subdivisions perpendicular to the long axis of the brain can be seen early in development. These are termed rhombomeres (neuromeres) to note their segmental arrangement (Muller and O’Rahilly 1997). At stage 9, six primary rhombomeres can be seen. Up to 16 secondary segments can be identified at stage 14. Eight main rhombomeres are recognized extending from the midbrain–hindbrain boundary rostrally to the spinal cord caudally (see Fig. 3.3). Rhombomeres 8 and 7 give rise to crest cells that migrate into the fourth and sixth pharyngeal arches; rhombomere 6 crest invades the third pharyngeal arch. Rhombomere 4 crest migrates into the second arch, whereas rhombomeres 5 and 3 give rise to a very small number of neural crest cells that migrate rostrally and caudally to enter the adjacent even-numbered neighbours. Rhombomeres 1 and 2 produce crest that invades the first pharyngeal arch. In each case mesenchymal populations and the sensory and autonomic ganglia are formed from the crest cells.

Further rostrally, neural crest from the mesencephalon migrates into the first arch maxillary and mandibular processes. Crest cells are produced from the diencephalon up to the level of the epiphysis. Neural crest cells produced from this rostral portion of the brain contribute mesenchymal populations to the frontonasal process. The most rostral prosencephalic neural fold does not give rise to neural crest; it produces cells that either remain epithelial as placodes or form the epithelial lining of the nasal cavity.

Ectodermal Placodes

Prior to neural tube closure, the elevating neural folds contain two distinctive neuronal populations. The larger population of neural crest cells migrates from the neural epithelium prior to neural tube fusion. A smaller population of neuroepithelial cells becomes incorporated into the surface ectoderm after neural tube closure. These areas of neuroepithelium within the surface ectoderm are termed ectodermal placodes. Although the majority of the ectodermal placodes form nervous tissue, non-neurogenic placodes also occur (Begbie and Graham 2001). After an appropriate inductive stimulus, local clusters of placodal cells remove themselves from the surrounding surface ectoderm either by epithelial–mesenchymal transition or by invagination of the whole placodal region to form a vesicle beneath the remaining surface ectoderm. Neurogenic placodes undergo both processes. Paired non-neurogenic placodes invaginate to form the lens vesicles under the inductive influence of the optic vesicles.

The neural folds meet in the rostral midline adjacent to the buccopharyngeal membrane. This rostral neural fold does not generate neural crest but gives rise to the hypophysial placode (i.e. the future Rathke’s pouch), which remains within the surface ectoderm directly rostral to the buccopharyngeal membrane. The rostral neural fold also gives rise to the olfactory placodes (which remain as paired, laterally placed placodes) and to the epithelium of the nasal cavity (see Fig. 3.11).

Further caudally, similar neurogenic placodes can be identified and divided into three categories: ventrolateral or epibranchial, dorsolateral and intermediate (Fig. 3.13). The epibranchial placodes appear in the surface ectoderm immediately dorsal to the area of pharyngeal (branchial) cleft formation. The first epibranchial placode is located at the level of the first pharyngeal groove and contributes cells to the distal (geniculate) ganglion of the facial nerve; the second and third epibranchial placodes contribute cells to the distal ganglia of the glossopharyngeal (petrosal) and vagus (nodose) nerves, respectively. Generally these placodes thicken, and cells begin to detach from the epithelium soon after the pharyngeal pouches have contacted the overlying ectoderm. Concurrently the neural crest cells reach and move beyond these lateral extensions of the pharynx. Cells budding off placodes show signs of early differentiation into neurones, including the formation of neurites. Epibranchial placodes may have their origins in the neurones that innervate the taste buds in fishes.

Dorsolateral placodes may be related evolutionarily to the sensory receptors of the lateral line system of lower vertebrates. They are represented by the otic placodes, located lateral to the myelencephalon, and invaginate to form otic vesicles from which the membranous labyrinth of the ear develops. Neurones of the vestibulocochlear nerve ganglia arise by budding off the ventromedial aspect of the otic cup, after which they can be distinguished in the acoustic and vestibular ganglia.

Intermediate between the epibranchial and dorsolateral placodes are the profundal and trigeminal placodes, which fuse in humans to form a single entity. Prospective neuroblasts migrate from foci dispersed throughout the surface ectoderm lateral and ventrolateral to the caudal mesencephalon and metencephalon to contribute to the distal portions of the trigeminal ganglia.

Pituitary Gland (Hypophysis Cerebri)

The hypophysis cerebri consists of the adenohypophysis and the neurohypophysis. Prior to neurulation the cell populations that give rise to these two portions of the pituitary gland are found next to each other within the rostral portion of the floor of the neural plate and the contiguous midline neural fold. As neurulation proceeds the future neurohypophysis remains within the floor of the prosencephalon, and the cells of the future adenohypophysis are displaced into the surface ectoderm, where they form the hypophysial placode.

The most rostral portion of the neural plate, which will form the hypothalamus, is in contact rostrally with the future adenohypophysis, in the rostral neural ridge, and caudally with the neurohypophysis, in the floor of the neural plate (see Fig. 3.11). After neurulation the cells of the anterior neural ridge remain in the surface ectoderm and form the hypophysial placode, which is in close apposition and adherent to the overlying prosencephalon.

Neural crest mesenchyme later moves between the prosencephalon and surface ectoderm, except at the region of the placode. Before rupture of the buccopharyngeal membrane, proliferation of the periplacodal mesenchyme results in the placode forming the roof and walls of a saccular depression. This hypophysial recess (Rathke’s pouch; Figs. 3.14, 3.15) is the rudiment of the adenohypophysis. It lies immediately ventral to the dorsal border of the buccopharyngeal membrane, extending in front of the rostral tip of the notochord and retaining contact with the ventral surface of the prosencephalon. It is constricted by continued proliferation of the surrounding mesenchyme to form a closed vesicle, but it remains connected for a time to the ectoderm of the stomodeum by a solid cord of cells that can be traced down the posterior edge of the nasal septum. Masses of epithelial cells form mainly on each side and in the ventral wall of the vesicle, and development of the adenohypophysis progresses by the ingrowth of a mesenchymal stroma. Differentiation of epithelial cells into stem cells and three differentiating types is apparent during the early months of fetal development. It has been suggested that different types of cells arise in succession and that they may be derived in varying proportions from different parts of the hypophysial recess. A craniopharyngeal canal, which sometimes runs from the anterior part of the hypophysial fossa of the sphenoid to the exterior of the skull, often marks the original position of the hypophysial recess. Traces of the stomodeal end of the recess are usually present at the junction of the septum of the nose and the palate. Some claim that the craniopharyngeal canal itself is a secondary formation caused by the growth of blood vessels and that it is unconnected to the stalk of the anterior lobe.

A small endodermal diverticulum, called Sessel’s pouch, projects toward the brain from the cranial end of the foregut, immediately caudal to the buccopharyngeal membrane. In some marsupials this pouch forms a part of the hypophysis, but in humans it apparently disappears entirely.

Just caudal to, but in contact with, the adenohypophysial recess, a hollow diverticulum elongates toward the stomodeum from the floor of the neural plate just caudal to the hypothalamus (see Fig. 3.15B); this region of neural outgrowth is the neurohypophysis. It forms an infundibular sac, the walls of which increase in thickness until the contained cavity is obliterated except at its upper end, where it persists as the infundibular recess of the third ventricle. The neurohypophysis becomes invested by the adenohypophysis, which extends dorsally on each side of it. The adenohypophysis gives off two processes from its ventral wall that grow along the infundibulum and fuse to surround it, coming into contact with the tuber cinereum and forming the tuberal portion of the hypophysis. The original cavity of Rathke’s pouch remains first as a cleft and later as scattered vesicles; it can be identified readily in sagittal sections through the mature gland. The dorsal wall of Rathke’s pouch, which remains thin, fuses with the adjoining part of the neurohypophysis as the pars intermedia.

At birth the hypophysis is about one-sixth the weight of the adult gland; it increases to become about one-half the weight of the adult gland at 7 years and attains adult weight at puberty. Throughout postnatal life the gland is both larger and heavier in females.

Neuroglia

Glial cells that support neurones in the CNS and PNS are derived from three lineages: the neuroectoderm of the neural tube, the neural crest and the angioblastic mesenchyme. In the CNS, cells of the proliferating ventricular zone give rise to astrocyte and oligodendrocyte cell lines. After the proliferative phase, the cells remaining at the ventricular surface differentiate into ependymal cells, which are specialized in many regions of the ventricular system as circumventricular organs. In the PNS, neural crest cells produce Schwann cells and astrocyte-like support cells in the enteric nervous system. Angioblastic mesenchyme gives rise to a variety of blood cell types, including circulating monocytes that infiltrate the brain as microglial cells later in development.

The ventricular zone lining the early central canal of the spinal cord and the cavities of the brain gives rise to neurones and glial cells (see Figs. 3.4, 3.5). One specialized form of glial cell is the radial glial cell, whose radial processes extend both outward, to form the outer limiting membrane deep to the pia mater, and inward, to form the inner limiting membrane around the central cavity. The geometry of these cells may provide contact guidance paths for cell migrations, both neuroblastic and glioblastic. A secondary radial glial scaffold is formed in the late-developing cerebellum and dentate gyrus and serves to translocate neuroblasts, formed in secondary germinal centres, to their definitive adult locations. Radial glia eventually lose their connections with both inner and outer limiting membranes, except for those that persist in the retina as Müller cells, in the cerebellum as Bergmann glia and in the hypothalamus as tanycytes. They can differentiate into neurones as well as astrocytes. They may partially clothe the somata of neighbouring developing neurones (between presumptive synaptic contacts) or similarly enwrap the intersynaptic surfaces of their neurites. Glial processes may expand around intraneural capillaries as perivascular end-feet. Other glioblasts retain an attachment (or form new expansions) to the pia mater, the innermost stratum of the meninges, as pial end-feet. Glioblasts also line the central canal and cavities of the brain as generalized or specialized ependymal cells, but they lose their peripheral attachments. In some situations, such as in the anterior median fissure of the spinal cord, ependymal cells retain their attachments to both the inner and outer limiting membranes. Thus, glia function as perineuronal satellites and provide cellular channels interconnecting extracerebral and intraventricular cerebrospinal fluid, the cerebral vascular bed, the intercellular crevices of the neuropil and the cytoplasm of all neural cell varieties.

Microglia appear in the CNS after it has been penetrated by blood vessels and invade it in large numbers from certain restricted regions. From there they spread in what have picturesquely been called ‘fountains of microglia’ to extend deeply among the nervous elements.

Mechanisms of Neural Development

For more than a century the mechanisms that operate during development of the nervous system have been studied experimentally. Although much has been established, answers to many fundamental questions still remain obscure. In recent years, significant advances in our understanding of the development of vertebrates have come from work on amphibian, chicken, mouse and fish embryos and from the production of embryonic chimera (Le Douarin, Teillet and Catala, 1998). A combination of genetic, embryological, biochemical and molecular techniques has been used to elucidate the mechanisms operating in early neural populations.

The CNS has a fundamental structure of layers and cells that are all derived from a pluripotential neuroepithelium. Developing neuroblasts produce axons that traverse great distances to reach their target organs. Within the CNS they form myriad connections with other neuroblasts in response to locally secreted neurotrophins. The brain and spinal cord reveal an intrinsic metamerism, induced rostrally by genes and caudally by inductive influences from adjacent structures.

Histogenesis of the Neural Tube

The wall of the early neural tube consists of an internal ventricular zone (sometimes termed the germinal matrix) abutting the central lumen. It contains the nucleated parts of the pseudostratified columnar neuroepithelial cells and rounded cells undergoing mitosis. The early ventricular zone also contains a population of radial glial cells whose processes pass from the ventricular surface to the pial surface, thus forming the internal and external glia limitans (glial limiting membrane). As development proceeds, the early pseudostratified epithelium proliferates, and an outer layer (the marginal zone), devoid of nuclei but containing the external cytoplasmic processes of cells, is delineated. Subsequently, a middle mantle layer (the intermediate zone) forms as the progeny from the ventricular zone migrate ventriculofugally (see Fig. 3.5).

Most CNS cells are produced in the proliferative zone adjacent to the future ventricular system, and in some regions this area is the only actively mitotic zone. According to the monophyletic theory of neurogenesis, it is assumed to produce all cell types. The early neural epithelium, including the deeply placed ventricular mitotic zone, consists of a homogeneous population of pluripotent cells whose varying appearances reflect different phases in a proliferative cycle. The ventricular zone is considered to be populated by a single basic type of progenitor cell and to exhibit three phases. The cells show an ‘elevator movement’ as they pass through a complete mitotic cycle, progressively approaching and then receding from the internal limiting membrane (Fig. 3.16). DNA replication occurs while the cells are extended and their nuclei approach the pial surface; they then enter a premitotic resting period as the cells shorten and their nuclei pass back toward the ventricular surface. The cells now become rounded close to the internal limiting membrane and undergo mitosis. They then elongate, and their nuclei move toward the outer edge during the postmitotic resting period, after which DNA synthesis commences once more, and the cycle is repeated. The cells so formed may either start another proliferative cycle or migrate outward (i.e. radially) and differentiate into neurones as they approach and enter the adjacent stratum. This differentiation may be initiated as they pass outward during the postmitotic resting period. The proliferative cycle continues with the production of clones of neuroblasts and glioblasts. This sequence of events has been called interkinetic nuclear migration, and it eventually declines. At the last division, two postmitotic daughter cells are produced, and they differentiate at the ventricular surface into ependyma.

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Fig. 3.16 Cell cycle in the ventricular zone of the developing neural tube. The nuclei of the proliferating stem cells show interkinetic migration.

(From Fujita, S. 1963. J. Comp. Neurol. 120, 37–42. Reprinted by permission from Wiley-Liss Inc.)

The progeny of some of these divisions move away from the ventricular zone to form an intermediate zone of neurones. The early spinal cord and much of the brain stem shows only these three main layers: ventricular, intermediate and marginal zones. However, in the telencephalon, the region of cellular proliferation extends deeper than the ventricular zone, where the escalator movement of interkinetic migration is seen, and a subventricular zone appears between the ventricular and intermediate layers (see Fig. 3.5). Here cells continue to multiply to provide further generations of neurones and glia, which subsequently migrate into the intermediate and marginal zones. In some regions of the nervous system (e.g. the cerebellar cortex) some mitotic subventricular stem cells migrate across the entire neural wall to form a subpial population and establish a new zone of cell division and differentiation. Many cells formed in this site remain subpial in position, but others migrate back toward the ventricle through the developing nervous tissue and finish their migration in various definitive sites where they differentiate into neurones or macroglial cells. In the cerebral hemispheres, a zone termed the cortical plate is formed outside the intermediate zone by radially migrating cells from the ventricular zone. The most recently formed cells migrate to the outermost layers of the cortical plate, so that earlier formed and migrating cells become subjacent to those migrating later. In the forebrain there is an additional transient stratum deep to the early cortical plate, the subplate zone.

Lineage and Growth in the Nervous System

Neurones come from two major embryonic sources: CNS neurones originate from the pluripotential neural plate and tube, whereas ganglionic neurones originate from the neural crest and ectodermal placodes. The neural plate also provides ependymal and macroglial cells. Peripheral Schwann cells and chromaffin cells arise from the neural crest. The origins and lineages of cells in the nervous system have been determined experimentally by the use of autoradiography, by microinjection or retroviral labelling of progenitor cells and in cell culture.

During development, neurones are formed before glial cells. The timing of events differs in various parts of the CNS and between species. Most neurones are formed prenatally in mammals, but some postnatal neurogenesis does occur (e.g. the small granular cells of the cerebellum, olfactory bulb and hippocampus, and neurones of the cerebral cortex). Gliogenesis continues after birth in periventricular and other sites. Autoradiographic studies have shown that different classes of neurones develop at specific times. Large neurones, such as principal projection neurones, tend to differentiate before small ones, such as local circuit neurones. However, their subsequent migration appears to be independent of the time of their initial formation. Neurones can migrate extensively through populations of maturing, relatively static cells to reach their destination; for example, cerebellar granule cells pass through a layer of Purkinje cells en route from the external pial layer to their final central position. Later, the final form of their projections, their cell volume and even their continuing survival depend on the establishment of patterns of functional connection.

Initially, immature neurones, termed neuroblasts, are rotund or fusiform. Their cytoplasm contains a prominent Golgi apparatus, many lysosomes, glycogen and numerous unattached ribosomes. As maturation proceeds, cells send out fine cytoplasmic processes that contain neurofilaments, microtubules and other structures, often including centrioles at their bases where microtubules form. Internally, endoplasmic reticulum cisternae appear, and attached ribosomes and mitochondria proliferate, whereas the glycogen content progressively diminishes. One process becomes the axon, and other processes establish a dendritic tree. Axonal growth, studied in tissue culture, may be as much as 1 mm per day.

Growth Cones

Ramón y Cajal (1890) was the first to recognize that the expanded end of an axon, the growth cone, is the principal sensory organ of the neurone. The growing tips of neuroblasts have been studied extensively in tissue culture. Classically, the growth cone is described as an expanded region that is constantly active, changing shape, extending and withdrawing small filopodia and lamellipodia that apparently ‘explore’ the local environment for a suitable surface along which extension can occur. These processes are stabilized in one direction, determining the direction of future growth, and after consolidation of the growth cone, the exploratory behaviour recommences. This continuous cycle resembles the behaviour at the leading edge of migratory cells such as fibroblasts and neutrophils. The molecular basis of this behaviour is the transmission of signals external to the growth cone via cell surface receptors to the scaffolding of microtubules and neurofilaments within the axon. Growing neuroblasts have a cortex rich in actin associated with the plasma membrane, along with a core of centrally located microtubules and sometimes neurofilaments. The assembly of these components, as well as the synthesis of new membrane, occurs in segments distal to the cell body and behind the growth cone, although some assembly of microtubules may take place near the cell body.

The driving force of growth cone extension is uncertain. One possible mechanism is that tension applied to objects by the leading edge of the growth cone is mediated by actin, and local accumulations of F-actin redirect the extension of microtubules. Under some culture conditions, growth cones can develop mechanical tension, pulling against other axons or the substratum to which they are attached. It is possible that tension in the growth cone acts as a messenger to mediate the assembly of cytoskeletal components. Adhesion to the substratum appears to be important for consolidation of the growth cone and elaboration of the cytoskeleton in that direction.

During development, the growing axons of neuroblasts navigate with precision over considerable distances, often pursuing complex courses to reach their targets. Eventually they make functional contact with their appropriate end-organs (neuromuscular endings, secretomotor terminals, sensory corpuscles or synapses with other neurones). During the outgrowth of axonal processes, the earliest nerve fibres are known to traverse appreciable distances over an apparently virgin landscape, often occupied by loose mesenchyme. A central problem for neurobiologists, therefore, has been understanding the mechanisms of axon guidance (Gordon-Weeks 2000). Axon guidance is thought to involve short-range local guidance cues and long-range diffusible cues, any of which can be either attractive and permissive for growth or repellent and inhibitory. Short-range cues require factors that are displayed on cell surfaces or in the extracellular matrix; for example, axon extension requires a permissive, physical substrate, the molecules of which are actively recognized by the growth cone. They also require negative cues that inhibit the progress of the growth cone. Long-range cues come from gradients of specific factors diffusing from distant targets, which cause neurones to turn their axons toward the source of the attractive signal. The evidence for this has come from in vitro co-culture studies. The floor plate of the developing spinal cord exerts a chemotropic effect on commissural axons that later cross it, whereas there is chemorepulsion of developing motor axons from the floor plate. These forces are thought to act in vivo in concert in a dynamic process to ensure the correct passage of axons to their final destinations and to mediate their correct bundling together en route.

Dendritic Tree

Once growth cones have arrived in their general target area, they have to form terminals and synapses. In recent years, much emphasis has been placed on the idea that patterns of connectivity depend on the death of inappropriate cells. Programmed cell death, or apoptosis, occurs during the period of synaptogenesis if neurones fail to acquire sufficient amounts of specific neurotrophic factors. Coincident firing of neighbouring neurones that have found the appropriate target region might be involved in eliciting the release of these factors, thus reinforcing correct connections. Such mechanisms may explain the numerical correspondence between neurones in a motor pool and the muscle fibres innervated. On a subtler level, pruning of collaterals may give rise to mature neuronal architecture. The projections of pyramidal neurones from the motor and visual cortices, for example, start out with a similar architecture; the mature repertoire of targets is produced by the pruning of collaterals, leading to loss of projections to some targets.

The final growth of dendritic trees is also influenced by patterns of afferent connections and their activity. If deprived of afferents experimentally, dendrites fail to develop fully and, after a critical period, may become permanently affected even if functional inputs are restored (e.g. in the visual systems of young animals that have been visually deprived). This is analogous to the results of untreated amblyopia in infants. Metabolic factors also affect the final branching patterns of dendrites; for instance, thyroid deficiency in perinatal rats results in a small size and restricted branching of cortical neurones. This may be analogous to the mental retardation of cretinism.

Once established, dendritic trees appear to be remarkably stable, and partial deafferentation affects only dendritic spines or similar small details. As development proceeds, plasticity is lost, and soon after birth a neurone is a stable structure with a reduced rate of growth.

Neurotrophins

If neurones lose all afferent connections or are totally deprived of sensory input, there is atrophy of much of the dendritic tree or even the whole soma. Different regions of the nervous system vary quantitatively in their responses to such anterograde transneuronal degeneration. Similar effects occur in retrograde transneuronal degeneration. Thus, neurones are dependent on peripheral structures for their survival. Loss of muscles or sensory nerve endings, such as in the developing limb, results in reduced numbers of motor and sensory neurones. The specific factor produced by these target organs is termed nerve growth factor (NGF). NGF is taken into nerve endings and transported back to the neuronal somata. It is necessary for the survival of many types of neurones during early development and for the growth of their axons and dendrites, and it promotes the synthesis of neurotransmitters and enzymes. Antibodies to NGF cause the death of neuronal subsets when they reach their targets, and added NGF rescues neurones that would otherwise die. Since the discovery of NGF, several other trophic factors have been identified, including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4/5.

Neurotrophins exert their survival effects selectively on particular subsets of neurones. NGF is specific to sensory ganglion cells from the neural crest, sympathetic postganglionic neurones and basal forebrain cholinergic neurones. BDNF promotes the survival of retinal ganglion cells, motor neurones, sensory proprioceptive and placode-derived neurones, such as those of the nodose ganglion, which are unresponsive to NGF. NT-3 has effects on motor neurones and both placode- and neural crest–derived sensory neurones. Other growth factors that influence the growth and survival of neural cells include the fibroblast growth factors (FGFs) and ciliary neurotrophic factor (CNTF), all of which are unrelated in sequence to the NGF family. Members of the FGF family support the survival of embryonic neurones from many regions of the CNS. CNTF may control the proliferation and differentiation of sympathetic ganglion cells and astrocytes.

Each of the neurotrophins binds specifically to certain receptors on the cell surface. The receptor termed p75NTR binds all the neurotrophins with similar affinity. By contrast, members of the family of tyrosine kinase receptors bind with higher affinity and display binding preferences for particular neurotrophins. However, the presence of a tyrosine kinase receptor seems to be required for p75NTR function.

Nervous tissue influences the metabolism of its target tissues. If, during development, a nerve fails to connect with its muscle, both degenerate. If the innervation of slow (red) or fast (white) skeletal muscle is exchanged, the muscles change structure and properties to reflect the new innervation, indicating that the nerve determines muscle type, not vice versa.

Induction and Patterning of the Brain and Spinal Cord

The generation of neural tissue involves an inductive signal from the underlying chordamesoderm (notochord), termed the organizer. The observation by Spemann in 1925 that, in intact amphibian embryos, the presence of an organizer causes ectodermal cells to form nervous tissue, whereas in its absence they form epidermis, led to the discovery of neural induction. However, experiments performed much later in the century revealed that when ectodermal cells are dissociated, they also give rise to neural tissue. The paradox was resolved by the finding that intact ectodermal tissue is prevented from becoming neural by an inhibitory signal that is diluted when cells are dissociated. Many lines of evidence now indicate that this inhibitory signal is mediated by members of a family of secreted proteins, the bone morphogenetic proteins (BMPs). These molecules are found throughout ectodermal tissue during early development, and their inhibitory effect is antagonized by several neural inducers that are present within the organizer: noggin, chordin and follistatin. Each of these factors is capable of blocking BMP signalling, in some cases by preventing it from binding to its receptor.

The regional pattern of the nervous system is induced before and during neural tube closure. Early concepts about regional patterning envisaged that regionalization within mesenchymal populations that transmit inductive signals to the ectoderm imposes a similar mosaic of positional values on the overlying neural plate. For example, transplantation of caudal mesenchyme beneath the neural plate in Amphibia induced spinal cord, whereas rostral mesenchyme induced brain, as assessed by the morphology of the neuroepithelial vesicles. However, later work indicated a more complex scenario in which organizer grafts from early embryos induced mainly head structures, whereas later grafts induced mainly trunk structures. Subsequent molecular data tend to support a model in which neural-inducing factors released by the organizer, such as noggin, chordin and follistatin, neuralize the ectoderm and promote a mainly rostral neural identity. Later secreted signals then act to caudalize this rostral neural tissue, setting up an entire array of axial values along the neural tube. Candidates for these later caudalizing signals include retinoic acid, FGFs, and the WNT secreted proteins, which are present in the paraxial mesenchyme and later in its derivatives, the somites. This combination of signals does not seem to be sufficient to produce the most rostral forebrain structures. Other secreted proteins resident in the rostralmost part of the earliest ingressing axial populations of endoderm and mesenchyme are also capable of inducing markers of forebrain identity from ectodermal cells (Withington, Beddington and Cooke 2001).

As the neural tube grows and its shape is modified, a number of mechanisms refine the crude rostrocaudal pattern imposed during neurulation. Molecules that diffuse from tissues adjacent to the neural tube, such as the somites, have patterning influences. The neural tube possesses a number of intrinsic signalling centres, such as the midbrain–hindbrain boundary, which produce diffusible molecules capable of influencing tissue development at a distance. In this way extrinsic and intrinsic factors serve to subdivide the neural tube into a number of fairly large domains, on which local influences can then act. Domains are distinguished by their expression of particular transcription factors, which in many cases have been causally related to the development of particular regions. Examples of such genes are the Hox family, which are expressed in the spinal cord and hindbrain, and the Dlx, Emx and Otx families of genes, which are expressed in various regions of the forebrain. These are all developmental control genes that lie high up in the hierarchy and are capable of initiating cascades of expression of other genes to create a more fine-grained pattern of cellular differentiation. In contrast to the aforementioned secreted molecules, these genes encode proteins that are retained in the cell nucleus and thus can act on DNA to induce or repress further gene expression.

Segmentation in the Neural Tube

One mechanism involved in the process of regional differentiation of cell populations within the neural tube is segmentation, which is conspicuous in humans and other vertebrates in the serial arrangement of the vertebrae and axial muscles and in the periodicity of the spinal nerves. In the last century, the possibility that the neural tube might be divided into segments or neuromeres was entertained, but some contended that the bulges observed in the lateral walls of the neural tube were artifacts or were caused by mechanical deformation of the tube by adjacent structures. Recent years have seen a resurgence of interest in this subject and a detailed evaluation of the significance of neuromeres. A series of eight prominent bulges that appear bilaterally in the rhombencephalic wall early in development have been termed rhombomeres (see Fig. 3.3). (Whereas the term neuromere applies generally to putative ‘segments’ of the neural tube, the term rhombomere applies specifically to the rhombencephalon.) Many aspects of the patterning of neuronal populations and the elaboration of their axon tracts conform to a segmental plan, and rhombomeres have now been shown to constitute crucial units of pattern formation. Domains of expression of developmental control genes abut rhombomere boundaries, and perhaps most importantly, single-cell labelling experiments have revealed that cells within rhombomeres form segregated non-mixing populations (Fig. 3.17). The neural crest also shows intrinsic segmentation in the hindbrain and is segregated into streams at its point of origin in the dorsal neural tube. This may represent a mechanism whereby morphogenetic specification of the premigratory neural crest cells is conveyed to the pharyngeal arches. Although these segmental units lose their morphological prominence with subsequent development, they represent the fundamental ground plan of this part of the neuraxis, creating a series of semiautonomous units within which local variations in patterning can develop. The consequences of early segmentation for later developmental events, such as the formation of definitive neuronal nuclei within the brain stem, and of peripheral axonal projections remain to be explored.

Other brain regions are not segmented in quite the same way as the hindbrain. However, morphological boundaries, domains of cell lineage restriction and of cell mixing and regions of gene expression that abut sharp boundaries are found in the diencephalon and telencephalon. It is thus likely that compartmentation of cell groups with some, if not all, of the features of rhombomeres plays an important role in the formation of various brain regions.

The significance of intrinsic segmentation in the hindbrain is underlined by the absence of overt segmentation of the adjacent paraxial mesenchyme. There is no firm evidence for intrinsic segmentation in the spinal cord. Instead, segmentation of the neural crest, the motor axons and eventually the spinal nerves is dependent on segmentation of the neighbouring somites. Both neural crest cell migration and motor axon outgrowth occur through only the rostral, not the caudal, sclerotome of each somite, so dorsal root ganglia form only at intervals. The caudal sclerotome possesses inhibitory properties that deter neural crest cells and motor axons from entering. This illustrates the general principle that the nervous system is closely interlocked, in terms of morphogenesis, with the periphery—that is, surrounding non-nervous structures—and each is dependent on the other for its effective structural and functional maturation.

Genes such as the Hox and Pax gene families, which encode transcription factor proteins, show intriguing expression patterns within the nervous system. Genes of the Hox-b cluster, for example, are expressed throughout the caudal neural tube and up to discrete limits in the hindbrain that coincide with rhombomere boundaries. The ordering of these genes within a cluster on the chromosome (5′–3′) is the same as the caudal-to-rostral limits of expression of consecutive genes. This characteristic pattern is surprisingly similar in fish, frogs, birds and mammals. Hox genes play a role in patterning of not only the neural tube but also much of the head region, consistent with their expression in neural crest cells and within the pharyngeal arches. Disruption of the Hox a-3 gene in mice mimics DiGeorge syndrome, a congenital human disorder characterized by the absence (or near absence) of the thymus, parathyroid and thyroid glands; hypotrophy of the walls of the arteries derived from the aortic arches and subsequent conotruncal cardiac malformations. Some Pax genes are expressed in different dorsoventral domains within the neural tube. Pax-3 is expressed in the alar lamina, including the neural crest, whereas Pax-6 is expressed in the intermediate plate. The Pax-3 gene has the same chromosomal localization as the mouse mutation Splotch and the affected locus in the human Waardenburg’s syndrome, both of which are characterized by neural crest disturbances with pigmentation disorders and occasional neural tube defects. Both Hox and Pax genes have restricted expression patterns with respect to the rostrocaudal and dorsoventral axes of the neural tube, consistent with roles in positional specification. (For reviews of the expression patterns of these genes, see Krumlauf et al 1993.)

Whereas craniocaudal positional values are probably conferred on the neuroepithelium at the neural plate or early neural tube stage, dorsoventral positional values may become fixed later. The development of the dorsoventral axis is heavily influenced by the presence of the underlying notochord. The notochord induces the ventral midline of the neural tube, the floor plate. This specialized region consists of a strip of non-neural cells with distinctive adhesive and functional properties. Notochord and floor plate together participate in inducing the differentiation of the motor columns. Motor neurone differentiation occurs early, giving some support to the idea of a ventral-to-dorsal wave of differentiation. The notochord–floor plate complex may also be responsible for allotting the values of more dorsal cell types within the tube (see Fig. 3.7). For example, the dorsal domain of Pax-3 expression extends more ventrally in embryos experimentally deprived of notochord and floor plate, whereas grafting an extra notochord adjacent to the dorsal neural tube leads to the repression of Pax-3 expression.

Peripheral Nervous System

Somatic Nerves

Spinal Nerves

Each spinal nerve is connected to the spinal cord by a ventral root and a dorsal root (Fig. 3.18). The fibres of the ventral roots grow out from cell bodies in the anterior and lateral parts of the intermediate zone. These pass through the overlying marginal zone and external limiting membrane. Some enter the myotomes of the somites, and some penetrate the somites, reaching the adjacent somatopleure; in both sites they ultimately form the α-, β- and γ-efferents. At appropriate levels these are accompanied by the outgrowing axons of preganglionic sympathetic neuroblasts (segments T1–L2) or preganglionic parasympathetic neuroblasts (S2–4).

The fibres of the dorsal roots extend from cell somata in dorsal root ganglia into the spinal cord and also into the periphery. Neural crest cells are produced continuously along the length of the spinal cord, but gangliogenic cells migrate only into the rostral part of each somitic sclerotome, where they condense and proliferate to form a bilateral series of oval-shaped primordial spinal ganglia (dorsal root ganglia; see Fig. 3.12). Negative factors in the caudal sclerotome deter neural crest from entering. The rostral sclerotome has a mitogenic effect on the crest cells that settle within it. From the ventral region of each ganglion, a small part separates to form sympathochromaffin cells, whereas the remainder becomes a definitive spinal ganglion (dorsal root ganglion). The spinal ganglia are arranged symmetrically at the sides of the neural tube and, except in the caudal region, are equal in number to the somites. The cells of the ganglia, like the cells of the intermediate zone of the early neural tube, are glial and neuronal precursors. The glial precursors develop into satellite cells (which become closely applied to the ganglionic nerve cell somata), Schwann cells and possibly other cells. The neuroblasts, which are initially round or oval, soon become fusiform, and their extremities gradually elongate into central and peripheral processes. The central processes grow into the neural tube as the fibres of dorsal nerve roots, and the peripheral processes grow ventrolaterally to mingle with the fibres of the ventral root, thus forming a mixed spinal nerve. As development proceeds, the original bipolar form of the cells in the spinal ganglia changes, and the two processes become approximated until they ultimately arise from a single stem to form a unipolar cell. The bipolar form is retained in the ganglion of the vestibulocochlear nerve.

Cranial Nerves

Cranial nerves may contain motor, sensory or both types of fibres. With the exception of the olfactory and optic nerves, the cranial nerves develop in a manner similar in some respects to components of the spinal nerves. The somata of motor neuroblasts originate within the neuroepithelium; those of sensory neuroblasts are derived from the neural crest, with additional contributions in the head from ectodermal placodes (Fig. 3.19).

The motor fibres of the cranial nerves that project to striated muscle are the axons of cells originating in the basal plate of the midbrain and hindbrain. The functional and morphological distinction between the neurones within these various nerves is based on the types of muscle innervated. In the trunk, the motor roots of the spinal nerves all emerge from the spinal cord close to the ventral midline, to supply the muscles derived from the somites. In the head, the motor outflow is traditionally divided into two pathways (see Figs. 3.2B, 3.19). General somatic efferent neurones exit ventrally in a similar manner to those of the spinal cord. Thus the oculomotor, trochlear, abducens and hypoglossal nerves parallel the organization of the somatic motor neurones in the spinal cord. The second motor component, the special branchial efferent, consists of the motor parts of the trigeminal, facial, glossopharyngeal and vagus nerves, which supply the pharyngeal (branchial) arches and the accessory nerve. All these nerves have nerve exit points more dorsally placed than in the somatic motor system.

The cranial nerves also contain general visceral efferent neurones (parasympathetic preganglionic neurones) that travel in the oculomotor, facial, glossopharyngeal and vagus nerves and leave the hindbrain via the same exit points as the special branchial efferent fibres. All three categories of motor neurones probably originate from the same region of the basal plate, adjacent to the floor plate. The definitive arrangement of nuclei reflects the differential migration of neuronal somata. It is not known whether all these cell types share a common precursor within the rhombencephalon; however, in the spinal cord, somatic motor and preganglionic autonomic neurones are linearly related.

These motor neurone types have been designated according to the types of muscles or structures they innervate. General somatic efferent nerves supply striated muscle derived from the cranial (occipital) somites and prechordal mesenchyme. Myogenic cells from the ventrolateral edge of the epithelial plate of occipital somites give rise to the intrinsic muscles of the tongue, and the prechordal mesenchyme gives rise to the extrinsic ocular muscles. Special branchial efferent nerves supply the striated muscles developing within the pharyngeal (branchial) arches, which are derived from parachordal mesenchyme between the occipital somites and the prechordal mesenchyme. All the voluntary muscles of the head originate from axial (prechordal) or paraxial mesenchyme, which renders the distinction between somatic efferent supply and branchial efferent supply somewhat artificial. However, because of the obviously special nature of the arch musculature, its patterning by the neural crest cells, its particularly rich innervation for both voluntary and reflex activity and the different origins from the basal plate of the branchial efferent nerves compared with the somatic efferent nerves, the distinction between the two is of some value.

General visceral efferent neurones (parasympathetic preganglionic neurones) innervate the glands of the head, the sphincter pupillae and ciliary muscles and the thoracic and abdominal viscera.

The cranial sensory ganglia are derived in part from the neural crest and in part from cells of the ectodermal placodes (see Figs. 3.13, 3.19). Generally, neurones distal to the brain are derived from placodes, and proximal ones are derived from the neural crest (see Fig. 3.19). Supporting cells of all sensory ganglia arise from the neural crest. The most rostral sensory ganglion, the trigeminal, contains both neural crest– and placode-derived neurones that mediate general somatic afferent functions. The same applies to the more caudal cranial nerves (facial, glossopharyngeal, vagus), but the two cell populations form separate ganglia in the case of each nerve. The proximal series of ganglia is derived from neural crest (forming the proximal ganglion of the facial nerve, the superior ganglion of the glossopharyngeal nerve and the jugular ganglion of the vagus nerve); the distal series is derived from placodal cells (forming the geniculate ganglion of the facial nerve, the petrosal ganglion of the glossopharyngeal nerve and the nodose ganglion of the vagus nerve). These ganglia contain neurones that mediate special, general visceral and somatic afferent functions. The vestibulocochlear nerve has a vestibular ganglion that contains both crest and placodal cells and an acoustic ganglion from placodal neurones only; it conveys special somatic afferents.

The neurones and supporting cells of the cranial autonomic ganglia in the head and trunk originate from neural crest cells. Caudal to the ganglion of the vagus nerve, the occipital region of the neural crest is concerned with the ‘ganglia’ of the accessory and hypoglossal nerves. Rudimentary ganglion cells may occur along the hypoglossal nerve in the human embryo; they subsequently regress. Ganglion cells are found on the developing spinal root of the accessory nerve, and these are believed to persist in the adult. The central processes of the cells of these various ganglia, where they persist, form some sensory roots of the cranial nerves and enter the alar lamina of the hindbrain. Their peripheral processes join the efferent components of the nerve to be distributed to the various tissues innervated. Some incoming fibres from the facial, glossopharyngeal and vagus nerves collect to form an oval bundle, the tractus solitarius, on the lateral aspect of the myelencephalon. This bundle is the homologue of the oval bundle of the spinal cord, but in the hindbrain it becomes more deeply placed by the overgrowth, folding and subsequent fusion of tissue derived from the rhombic lip on the external aspect of the bundle.

Autonomic Nervous System

Autonomic nerves, apart from the preganglionic motor axons arising from the CNS, are formed by the neural crest. The autonomic nervous system includes the sympathetic and parasympathetic neurones in the peripheral ganglia and their accompanying glia, the enteric nervous system and glia and the suprarenal medulla.

In the trunk at neurulation, neural crest cells migrate from the neural epithelium to lie transitorily on the fused neural tube. Thereafter, crest cells migrate laterally and then ventrally to their respective destinations (see Fig. 3.12). In the head, the neural crest cells migrate prior to neural fusion, producing a vast mesenchymal population as well as autonomic neurones.

The four major regions of neural crest cell distribution to the autonomic nervous system are cranial, vagal, trunk and lumbosacral. The cranial neural crest gives rise to the cranial parasympathetic ganglia, whereas the vagal neural crest gives rise to the thoracic parasympathetic ganglia. The trunk neural crest gives rise to the sympathetic ganglia, mainly the paravertebral ganglia, and suprarenomedullary cells. This category is often referred to as the sympathoadrenal lineage.

Neurones of the enteric nervous system are described as arising from the vagal crest—that is, the neural crest derived from somite levels 1 to 7, and the sacral crest caudal to the twenty-eighth somite. At all these levels the crest cells also differentiate into glial-like support cells alongside the neurones (Fig. 3.20).

Parasympathetic Ganglia

Neural crest cells migrate from the region of the mesencephalon and rhombencephalon prior to neural tube closure. From rostral to caudal, three populations of neural crest are described: cranial neural crest, cardiac neural crest and vagal neural crest. Migration of the sacral neural crest and formation of the caudal parasympathetic ganglia have attracted little research interest.

Neural crest cells from the caudal third of the mesencephalon and the rostral metencephalon migrate along or close to the ophthalmic branch of the trigeminal nerve and give rise to the ciliary ganglion. Cells migrating from the nucleus of the oculomotor nerve may also contribute to the ganglion; a few scattered cells are always demonstrable in postnatal life along the course of this nerve. Preotic myelencephalic neural crest cells give rise to the pterygopalatine ganglion, which may also receive contributions from the ganglia of the trigeminal and facial nerves. The otic and submandibular ganglia are also derived from myelencephalic neural crest and may receive contributions from the glossopharyngeal and facial cranial nerves, respectively.

Neural crest from the region located between the otic placode and the caudal limit of somite 3 has been termed cardiac neural crest. Cells derived from these levels migrate through pharyngeal arches 3, 4 and 6, where they provide, among other things, support for the embryonic aortic arch arteries, cells of the aorticopulmonary septum and truncus arteriosus. Some of these neural crest cells also differentiate into the neural anlage of the parasympathetic ganglia of the heart. Sensory innervation of the heart is from the inferior ganglion of the vagus, which is derived from the nodose placodes. Neural crest cells migrating from the level of somites 1 to 7 are collectively termed vagal neural crest; they migrate to the gut along with the sacral neural crest.

Sympathetic Ganglia

Neural crest cells migrate ventrally within the body segments to penetrate the underlying somites and continue to the region of the future paravertebral and prevertebral plexuses, notably forming the sympathetic chain of ganglia as well as the major ganglia around the ventral visceral branches of the abdominal aorta (see Figs. 3.12, 3.20).

There is cell-specific recognition of postganglionic neurones and the growth cones of sympathetic preganglionic neurones. They meet during growth, and this may be important in terms of guidance to their appropriate target. The position of postganglionic neurones, and the exit point from the spinal cord of preganglionic neurones, may influence the types of synaptic connections made and the affinity for particular postganglionic neurones. When a postganglionic neuroblast is in place, it extends axons (and dendrites), and synaptogenesis occurs. The earliest axonal outgrowths from the superior cervical ganglion occur at about stage 14; although the axon is the first cell process to appear, the position of the neurones apparently does not influence the appearance of the cell processes.

The local environment is the major factor that controls the appropriate differentiation of the presumptive autonomic ganglion neurones. The factors responsible for subsequent adrenergic, cholinergic or peptidergic phenotype have yet to be identified, although it has been proposed that fibronectin and basal lamina components initiate adrenergic phenotypical expression at the expense of melanocyte numbers. Cholinergic characteristics are acquired relatively early, and the appropriate phenotypical expression may be promoted by cholinergic differentiation factor and CNTF.

Neuropeptides are expressed by autonomic neurones in vitro and may be stimulated by various target tissue factors in sympathetic and parasympathetic neurones. Some neuropeptides are expressed more intensely during early stages of ganglion formation.

Enteric Nervous System

The enteric nervous system is different from the other components of the autonomic nervous system because it can mediate reflex activity independently of control by the brain and spinal cord. The number of enteric neurones that develop is believed to be of the same magnitude as the number of neurones in the spinal cord. Preganglionic fibres that supply the intestine, and therefore modulate the enteric neurones, are much fewer.

The enteric nervous system is derived from the neural crest. The axial levels of crest origin are shown in Figure 3.20. Premigratory neural crest cells are not prepatterned for specific axial levels; rather, they attain their axial value as they leave the neuraxis. Once within the gut wall, there is a regionally specific pattern of enteric ganglia formation that may be controlled by the local splanchnopleuric mesenchyme. Cranial neural crest from somite levels 1 to 7 contributes to the enteric nervous system, forming both neuroblasts and glial support cells.

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