Chapter 16 Towards the end of the third week of embryological development in domestic animals, the notochord induces the overlying columnar ectodermal cells of the embryonic disc to become pseudostratified neuroepithelial cells and form a spoon‐shaped thickening called the neural plate. The cranially‐expanded region of the neural plate forms the primordium of the brain, while the narrower region, caudal to the brain primordium, gives rise to the neural tube. The raised lateral edges of the neural plate form the neural folds, while the depressed midline region of the plate forms a groove, termed the neural groove (Fig 16.1). Following progressive changes in the columnar neuroepithelium, folding of the neural plate occurs. The cells overlying the notochord become wedge‐shaped, with their bases positioned on the basal lamina. These changes contribute to the neural plate becoming a V‐shaped structure with a midline ventral axis. The neuroepithelial cells in contact with the surface ectodermal cells also become wedge‐shaped with their apices positioned on the basal lamina. Cellular proliferation at the medial aspects of the neural folds causes these structures to gradually approach each other in the midline, meet and fuse, forming the neural tube which encloses a central neural canal (Fig 16.2). Closure of the neural tube commences at the level of the fourth somite and, from this point, progresses cranially and caudally in a manner similar to the action of a zip fastener. The cranial and caudal ends of the neural tube, which remain patent for a time, are termed the rostral and caudal neuropores respectively. For a short time prior to closure of the neuropores, the neural canal communicates directly with the amniotic cavity. As the developing brain and spinal cord have a limited vascular supply at this stage in their development, it has been suggested that these structures receive their supply of nutrients from the amniotic fluid through the neuropores. The rostral neuropore closes midway through the embryonic period with closure of the caudal neuropore occurring shortly afterwards. Subsequently, the neural tube loses its connection with the surface ectoderm and occupies a position ventral to the surface ectoderm. The process whereby the neural tube forms by folding, primary neurulation, extends from the rostral neuropore to the caudal neuropore. Figure 16.1 Dorsal view of a developing embryo at the stage when neurulation commences. Figure 16.2 Sections through the embryo at sequential stages of primary neurulation. A. Formation of the neural groove and location of neural crest cells. B. Formation of neural folds. C. Formation of the neural tube. Formation of the neural tube in the sacral and caudal regions of the developing embryo occurs through a process referred to as secondary neurulation. A solid column of mesenchymal cells, derived from the primitive streak in the caudal region of the developing embryo, fuses with the closed caudal end of the neural tube. A central canal in this cord of cells, formed by cavitation, becomes continuous with the neural canal formed during primary neurulation. The length of the region of the spinal cord which arises from secondary neurulation is closely related to the number of caudal vertebrae in a given species and, accordingly, is comparatively long in animals with long tails and short in higher primates. The initial patterning of the central nervous system is regulated by a small number of evolutionary‐conserved signalling factor families, including Bmp, Wnt, Shh, Fgf and retinoic acid, which are expressed as gradients along the cranial–caudal and dorsal—ventral axes. The same signalling molecules can induce different effects depending on their concentration, temporal and spatial expression and abundance of relevant receptor families and modulating factors. These factors contribute to the development of the gross anatomical structures which comprise the nervous system as well as promoting the differentiation of neural cell subtypes from their pluripotent state. When the neural plate has been induced to undergo neurulation by the underlying mesoderm, development of the neural tube commences. Two signalling centres, one located in the overlying ectoderm and the other in the notochord, influence the development and formation of the neural tube. Roof plate development is influenced by Bmp‐4 and Bmp‐7 produced by surface ectoderm. The floor plate of the neural tube is influenced by Shh signals from the notochord. At a later stage of development, secondary signalling centres are established within the neural tube itself (Fig 16.3). Bmp‐4 is expressed and secreted by the roof plate cells and Shh is also expressed in the floor plate cells. Bmp‐4 triggers a nested cascade of Tgf‐β factors which diffuse ventrally into the neural tube, while Shh diffuses dorsally. The neural tube is exposed to gradients of these signalling molecules along the dorsal—ventral axis (Fig 16.3). Depending on their position along the dorso‐ventral axis, cells are exposed to different concentrations of these signalling molecules which influence expression of transcription factors along this axis. Accordingly, cells located near the floor plate which are exposed to high concentrations of Shh and relatively low concentrations of Tgf‐β signals synthesise Nkx‐6.1 and Nkx‐2.2 and become determined and differentiate into ventral neurons. Cells located in a dorsal position are exposed to low levels of Shh and high levels of Tgf‐β, and hence different fate‐determining transcription factors are expressed by these cells. Figure 16.3 Dorsal—ventral patterning during formation of the neural tube. During fusion of the neural folds, a population of specialised cells derived from neuroepithelium develops along the lateral margins of the neural folds at the interface between the neural and surface ectoderm. These cells are specified by the bone morphogenetic proteins produced at the boundary between the neural plate and surface ectoderm, together with Wnt‐6 from the presumptive epidermis differentiating into neural crest cells. When induced by these factors, the neuroepithelial cells change their characteristics to those of mesenchyme‐like cells and penetrate the basal lamina of the neural plate. In the presence of Wnt, Fgf proteins, Bmp‐4 and Bmp‐7, expression of Slug and RhoB is induced in these specialised cells. Both Slug and RhoB are believed to have a role in neural crest cell migration. It has also been suggested that the RhoB protein may be involved in cytoskeletal alterations which facilitate migration, and that Slug protein activates factors which dissociate tight junctions between adjacent cells. During neural crest cell migration, the cell adhesion protein, N‐cadherin, is down‐regulated. As neural crest cells migrate from the developing neural tube, they form segmental cellular aggregations in a dorsal position which extend along the length of the neural tube on either side. The microenvironment of the extracellular matrix influences migration of the neural crest cells. A number of proteins including fibronectin, laminin, tenascin and certain collagen molecules promote this migration, whereas ephrin proteins impede migration. Other factors, such as stem cell factor, allow the continued proliferation of the neural crest cells. A single pluripotent neural crest cell can differentiate into many cell types depending on its location within the early embryo. During neural crest cell migration, exposure to different concentrations of the Bmp and Wnt signalling factors can influence their determination in becoming defined cell types. Derivatives of cranial and spinal neural crest cells are shown in Figure 16.4. Some derivatives of neural crest cells are not components of the nervous system. Neural components derived from neural crest cells include the spinal ganglia, autonomic ganglia and the glial cells of the peripheral nervous system (Fig 16.5). Figure 16.4 Derivatives of cranial and spinal neural crest cells. Figure 16.5 The origin and migratory pathways (arrows) of neural crest cells which arise from the thoraco‐lumbar region of the developing embryo, A. In their final location in the tissues, derivatives of these cells give rise to specialised cells and tissues, B. The neural tube is initially lined with pseudostratified columnar neuroepithelial cells which give rise to two cell types, neuronal and glial progenitor cells (Fig 16.6). Neuroblasts differentiate into the neurons of the central nervous system while gliablasts give rise to supporting cells. Following differentiation of neural epithelium, the neural tube consists of three distinct layers, an inner ependymal (ventricular) layer, a middle mantle (intermediate) layer and an outer marginal layer (Fig 16.7A). Neuroblasts in the early stage of differentiation have characteristic large round nuclei with pale‐staining nucleoplasm and prominent nucleoli. These cells, which migrate outwards from the ependymal layer, form the mantle layer. From this mantle layer, the grey matter of the spinal cord is formed. Cytoplasmic processes which extend laterally from the neuroblasts in the mantle layer contribute to the formation of the marginal layer of the neural tube. Gliablasts give rise to astrocytes, which are present in both the mantle and marginal layers, and oligodendrocytes, which mainly populate the marginal layer. In addition to the production of neuroblasts and cells of glial lineage, the neuroepithelium differentiates into ependymal cells which form the lining of the brain ventricles and the central canal of the spinal cord (Fig 16.6). The third supporting cell type of the nervous system, microglial cells, which are of mesenchymal origin and are actively phagocytic, arrive in the central nervous system after it becomes vascularised. Figure 16.6 Origin, differentiation and maturation of neurons, different types of glial cells and ependymal cells of the central nervous system. Figure 16.7 Cross‐sections through the neural tube at different stages of formation of the spinal cord. A. The three layers of the neural tube. B. Formation of the alar and basal plates in the developing spinal cord. C. Fusion of the alar and basal plates which form the grey matter of the spinal cord. Neuroblasts in the dorsal and ventral regions of the mantle layer on either side of the midline proliferate rapidly, resulting in the formation of the left and the right dorsal and ventral thickenings. The dorsal thickenings, which form the alar plates, are populated by neuroblasts (Fig 16.7B). Later, these neuroblasts become neurons, referred to as interneurons, which relay sensory impulses. Prominent ventral thickenings which form the basal plates are populated by neuroblasts which give rise to motor neurons. Left and right longitudinal grooves form along the inner wall of the central neural canal and each groove is referred to as a sulcus limitans. These grooves demarcate the boundary between the dorsal sensory alar plates and the ventral motor basal plates. Due to accelerated cell division, the alar and basal plates expand and the four plates fuse forming the characteristic butterfly‐shaped grey area evident in a cross‐section of the spinal cord (Fig 16.7C). During this process, the sulci disappear and the original large central canal of the neural tube becomes reduced in diameter. As a consequence of mitosis and hypertrophy of the cells of the basal plates, bilateral ventral bulging results in a deep median groove on the ventral surface of the spinal cord, referred to as the ventral fissure. A less prominent dorsal median groove also develops. The dorsal roof plate and the ventral floor plate of the neural tube, which do not contain neuroblasts, serve as pathways for fibres crossing from one side of the spinal cord to the other. In dorso‐lateral locations of the basal plate in the thoraco‐lumbar region, a group of neuroblasts divide, forming enlargements referred to as lateral horns. These neuroblasts, which differentiate into motor neurons, form part of the sympathetic division of the autonomic nervous system. Cells from the neural crest, which are distributed segmentally along the dorso‐lateral aspect of the left and right sides of the neural tube, give rise to the spinal ganglia which contain the nerve cell bodies of the afferent neurons of the peripheral nervous system. Neuroblasts in the basal plates differentiate, develop cytoplasmic processes and become motor neurons. A number of short processes, known as dendrites, arise at one pole of the neuroblast and, at the opposite pole, a single long process referred to as an axon develops. A nerve cell with more than one dendritic process is referred to as a multipolar neuron. From each segment of the spinal cord, axons grow out through the marginal layer of the cord and enter the vertebral canal. The ventral roots leave the vertebral canal through the intervertebral foramina on the side from which they derive and innervate effector organs. The sensory components of spinal nerves differentiate from neuroblasts in the spinal ganglia. Two cytoplasmic processes derive from each neuroblast in the spinal ganglia. One process extends into the dorsal horn of the spinal cord, and the other process, which leaves the vertebral canal by the intervertebral foramen, terminates in a sensory receptor in an organ such as the skin (Fig 16.8). In most instances, the sensory nerve processes within the dorsal horn form synapses with interneurons in the grey matter of the dorsal horn. These interneurons may form synapses with either ipsilateral ventral motor neurons or they may synapse with motor neurons on the contralateral ventral horn, forming, in both instances, multisynaptic reflex arcs. Occasionally, the processes from the spinal ganglia may form synapses directly with the motor neurons in the ventral horn of the cord and establish a monosynaptic reflex arc. Axons derived from interneurons may penetrate the marginal layer of the cord and extend cranially forming synapses at higher levels within the cord. Alternatively, they may continue as nerve fibre tracts forming synapses in brain nuclei. Both monosynaptic and multisynaptic reflex arcs participate in what is referred to as the general somatic system of innervation. Spinal nerves contain general somatic afferent and general somatic efferent fibres. In the development of the general visceral efferent component of spinal nerves, axons of the visceral motor neurons, which emerge from the lateral horn of the spinal cord, leave the vertebral canal via the intervertebral foramina and form synapses with neurons in ganglia of the autonomic nervous system. Post‐ganglionic autonomic fibres terminate in effector organs such as smooth muscle, cardiac muscle and glands. Thus, the visceral efferent system of a spinal nerve requires two neurons, in comparison with the somatic efferent system, which is a single‐neuron system (Fig 16.8). Figure 16.8 Formation of a spinal nerve. Right side shows a motor axon growing out from a cell body in the ventral horn of the developing spinal cord innervating an effector organ. One process from a neuroblast in a spinal ganglion grows into the dorsal horn of the developing spinal cord while the other process terminates in a somatic sensory receptor. Left side shows a motor axon growing out from a cell body in the lateral horn of the developing spinal cord towards an autonomic ganglion. Subsequently, axons grow out from the neuroblasts in the autonomic ganglion and terminate in effector organs. One process from a neuroblast in a spinal ganglion grows into the dorsal horn of the developing spinal cord while the other process terminates in a visceral sensory receptor. Autonomic ganglia develop from neural crest cells. In the general visceral efferent system, the axons of autonomic neurons located in the lateral horn of the spinal cord are referred to as pre‐ganglionic fibres. Axons, whose nerve cell bodies are located in autonomic ganglia, are referred to as post‐ganglionic fibres. A typical spinal nerve consists of a dorsal root comprising a large number of general somatic afferent fibres and general visceral afferent fibres, and a ventral root composed of general somatic efferent fibres and general visceral efferent fibres. Although dorsal afferent root fibres and ventral efferent root fibres intermingle at the intervertebral foramen, forming a spinal nerve which contains the four functional groups of fibres, each group remains distinct. On leaving the intervertebral foramen, a spinal nerve divides into a smaller dorsal and larger ventral branch. Each branch contains both somatic and visceral afferent and efferent fibres (Fig 16.8). Ventral branches of spinal nerves, especially in the cervico‐thoracic and lumbo‐sacral regions, form plexuses associated with the developing limb buds. That portion of the spinal cord between the fifth and seventh cervical vertebrae increases in diameter, almost filling the vertebral canal. This increase in size, referred to as the cervical intumescence, results from an increase in the number of neurons associated with innervation of the developing thoracic limbs. Similar enlargement in the lumbo‐sacral region, the lumbar intumescence, is associated with innervation of the developing pelvic limbs. Spinal nerves associated with the thoracic, lumbar, sacral and caudal regions of the vertebral column are assigned names related to the point at which they emerge from the vertebral canal through intervertebral foramina. The name assigned to a spinal nerve derives from the anatomical region of the vertebral column and the assigned number of the vertebra immediately cranial to the intervertebral foramen through which the spinal nerve passes. The first pair of thoracic nerves, which leave the intervertebral space caudal to the first thoracic vertebra, are designated the first thoracic spinal nerves (T1). Because there are eight spinal nerves in the cervical region and seven cervical vertebrae, this form of classification cannot be applied. The first pair of cervical spinal nerves pass through the lateral foramina of the atlas. The second pair of cervical spinal nerves pass through the first intervertebral foramina between the atlas and axis. Accordingly, the eighth cervical spinal nerves pass caudal to the seventh cervical vertebra. That region of the spinal cord from which the dorsal and ventral roots of a spinal nerve arise is termed a segment of the cord. A spinal cord segment is assigned a number corresponding to the spinal nerves arising from that segment. Schwann cells, neural crest‐derived neurilemmal cells, participate in the myelination of peripheral nerve fibres. In this process, neurilemmal cells are described as wrapping themselves around axons, forming a myelin sheath. The degree to which the neurilemmal cell becomes wrapped around the neuronal process determines whether a nerve fibre is classified as a myelinated nerve fibre or as a non‐myelinated nerve fibre. If the neurilemmal cell surrounds the nerve fibre and incorporates it into a deep invagination of the cell membrane, such a fibre is classified as non‐myelinated. Through this process, a number of nerve fibres may be enclosed by a single neurilemmal cell. When a single nerve fibre becomes enveloped by a neurilemmal cell which sequentially wraps itself around the fibre a number of times so that the fibre is enclosed in concentric layers of neurilemmal cytoplasm and plasma membrane, such a fibre is referred to as a myelinated fibre. In the process of myelination, the neurilemmal cell cytoplasm is extruded and the layered plasma membrane of the neurilemmal cell fuses, forming the myelin sheath. Towards the end of the embryonic period the spinal cord is the same length as the vertebral canal, and spinal nerves emerge from the vertebral column through the intervertebral foramina at levels corresponding to their points of origin. During the foetal period, however, the vertebral column grows at a faster rate than the spinal cord. Thus, in the late foetal period, the spinal cord is considerably shorter than the vertebral canal and in different species of domestic animals terminates at different levels in the lumbo‐sacral region. During this period of development, few if any neurons differentiate in the caudal end of the cord. Accordingly, the caudal extremity of the spinal cord tapers and forms a structure which is referred to as the conus medullaris. Caudal to the conus medullaris, the terminal portion of the spinal cord is composed of a cord‐like strand of glial and ependymal cells, the filum terminale, which attaches the conus medullaris to the caudal vertebrae (Fig 16.9). Due to the increased length of the vertebral canal relative to that of the spinal cord, the intervertebral foramina are positioned more caudally than the points of origin of the corresponding spinal nerves. As a result, the roots of the spinal nerves arising from the lumbar, sacral and caudal regions of the cord must pass caudally within the vertebral canal before emerging through the intervertebral foramina at points distant from their origins. Because of the anatomical appearance of the nerve roots, which extend in the vertebral canal caudally from their points of origin, they are collectively referred to as the cauda equina (Fig 16.9). Figure 16.9 Section through the dorsal plane of the caudal end of the vertebral column showing the cauda equina and filum terminale. Failure of the neural tube to close may arise from defective induction of the underlying notochord and from a range of teratogenic factors which adversely affect normal differentiation of the neuroepithelium. The defect may extend along the complete length of the neural tube or be restricted to a small region of the tube. Failure of neural tube closure adversely affects both differentiation of the nervous system and development of the vertebral column. Induction of the overlying vertebral arches is disrupted by failure of the neural tube to close. If the arches fail to fuse along the dorsal midline, the resulting open vertebral canal is referred to as spina bifida. While the term literally indicates a cleft in the spinal column, it can result in motor and sensory deficits and may predispose to a variety of severe clinical conditions including chronic infection. The defects associated with spina bifida range from minor anomalies of little clinical significance to more serious conditions which invariably lead to death of the affected animal (Fig 16.10). One form of the defect, which usually occurs in the lumbo‐sacral region, is called spina bifida occulta (Fig 16.10A). This defect results from failure of the vertebral arch of one or two vertebrae to close and, as a consequence, the dura mater is located subcutaneously. The spinal cord and roots of spinal nerves develop normally and neurological symptoms are usually absent. In humans, the only sign of this defect may be a small tuft of hair over the affected region. If more than two vertebrae are involved, and especially if the dura mater ruptures, the meninges are inclined to herniate through the opening, resulting in a prominent subcutaneous bulge containing the arachnoid membrane and cerebrospinal fluid. If the spinal cord and roots of spinal nerves remain in position and only the meninges and fluid herniate, the anomaly is referred to as meningocoele (Fig 16.10B). Minor neurological signs may be evident in meningocoele and the defect can be repaired surgically. When the spinal cord becomes displaced and occupies a position in the fluid‐filled arachnoid protrusion, the condition is known as meningomyelocoele (Fig 16.10C). Displacement of the spinal cord usually results in damage to the roots of the spinal nerves, causing neurological symptoms of varying severity. Complete failure of the neural tube to close, which is referred to as rachischisis, is invariably fatal (Fig 16.10D). Figure 16.10 Forms of spina bifida. A. Spina bifida occulta. B. Meningocoele. C. Meningomyelocoele. D. Myeloschisis and rachischisis resulting from failure of the neural tube to close and failure in the development of associated spinal structures. In the human population, it has been suggested that fertilisation of oocytes which are past the optimal time for fertilisation may lead to an increased incidence of neural tube anomalies. Prenatal diagnosis of spina bifida can be made by the detection of abnormally high levels of α‐foetoprotein in the amniotic fluid or by ultrasonography. The cranial expanded region of the neural plate gives rise to three dilations, the primary brain vesicles, namely the prosencephalon (forebrain), the mesencephalon (midbrain) and the rhombencephalon (hindbrain), outlined in Figure 16.11. In higher vertebrates, the compact nature of the brain and the relatively small space in which it develops are achieved through the formation of flexures and surface foldings as it is accommodated in the cranium. The ventral cranial flexure, which occurs in the midbrain region, is known as the cephalic flexure. The flexure between the hindbrain and the spinal cord is termed the cervical flexure. The prosencephalon gives rise rostrally to the telencephalon and caudally to the diencephalon. A narrow central canal persists in the mesencephalon. The rhombencephalon forms two dilations, the metencephalon and myelencephalon, both with dilated lumina (Table 16.1). A dorsal flexure, the pontine flexure, occurs between the metencephalon and the myelencephalon (Fig 16.11C). As the telencephalon expands dorsally and caudally, it overlies the diencephalon and mesencephalon, forming the cerebral hemispheres. Although there is no direct relationship between brain size and body size among non‐primates, in general, the brains of large terrestrial mammals are small relative to their body size. The brains of humans and non‐human primates are large relative to their body size. Figure 16.11 Left lateral views and sections through the dorsal plane of the developing brain. A. The three primary brain vesicles. B. Cephalic flexure and cervical flexure and development of the telencephalon and diencephalon. C. Pontine flexure and development of the metencephalon and myelencephalon. Table 16.1 Primary brain vesicles, brain subdivisions, their major derivatives and associated lumina.
Nervous system
Dorsal─ventral patterning of the neural tube
Neural crest
Differentiation of the cellular components of the neural tube
Development of glial cells
Development of neurons
Spinal nerves
Myelination of peripheral nerve fibres
The final position of the spinal cord relative to the developing vertebral column
Anomalies of the spinal cord
Differentiation of the brain subdivisions
Primary brain vesicles
Brain subdivisions
Major derivatives
Associated lumina
Prosencephalon (Forebrain)
Telencephalon
Cerebral cortex
Basal nuclei
Limbic system
Lateral ventricles
Mesencephalon (Midbrain)
Diencephalon
Epithalamus
Thalamus
Hypothalamus
Third ventricle
Rhombencephalon (Hindbrain)
Mesencephalon
Tectum
Corpora quadrigemina
Tegmentum
Cerebral peduncles
Mesencephalic aqueduct
Metencephalon
Pons
Cerebellum
Rostral part of fourth ventricle 
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