NEURAL TUBE

The central nervous system is a tubular structure originating from a proliferation of ectod ermal epithelial cells referred to as the neurectoderm, which is located dorsal to the notochord along the axis of the embryo. This thickened ectoderm, known as the neural plate, invaginates along this axis, forming a groove until the lateral extremities of the original plate, the neural folds, meet centrally and fuse over the neural groove to form a neural tube and canal. As the neural tube forms, it separates from the nonneural ectoderm which grows over the dorsum of the tube to fuse along the midline. As this fusion and separation of ectodermal layers occurs, a longitudinal column of ectodermal epithelial cells arises from the junction of nonneural and neural ectoderm and separates from these two structures when the neural tube is formed. These two bilateral columns, situated dorsolateral to the neural tube throughout its length, are the columns of neural crest cells (Fig. 3-1).

Figure 3-1 Development of the neural tube—transverse sections.

Closure of the neural tube progresses rostrally and caudally from the level of the site of development of the rhombencephalon, the most caudal division of the brain. The caudal closure forms the majority of the spinal cord. Closure of the brain portion of the neural tube may initially occur at multiple sites and progress rostrally and caudally. The locations of these sites vary among species of animals. Prior to complete closure, the most rostral opening is the rostral neuropore (Fig. 3-2). The caudal portion of the spinal cord develops from the caudal end of the closed neural tube as an extension of a column of neuroepithelial cells that grows caudally on the midline between the notochord and skin ectoderm. A cavitation of this column of cells produces an extension of the neural tube and its neural canal. This portion of the neural tube will ultimately form the caudal, the sacral, and a variable number of lumbar spinal cord segments. An opening may persist at the caudal end of the neural tube, allowing communication with the subarachnoid space of the leptomeninges at the conus medullaris.

Figure 3-2 Dorsal view of neural tube closure.

The rostral end of the neural tube develops rapidly and produces three vesicles, from rostral to caudal: the prosencephalon, mesencephalon, and rhombencephalon (Fig. 3-3). Early in its development the prosencephalon has lateral enlargements, the optic vesicles, which grow laterally to contact the overlying skin ectoderm. The further development of this primordial eye is described in Chapter 14, Visual System. Two additional swellings emerge from the rostral prosencephalon and grow out of the neural tube on each side laterally and dorsally. These telencephalic vesicles completely overgrow the original vesicular system and form the cerebral hemispheres. The portion of the prosencephalon that remains at the rostral end of the neural tube is the diencephalon. The optic vesicles remain associated with the diencephalon. The neural canal within the diencephalon is the third ventricle. It communicates rostrolaterally with the neural canal of each telencephalon (cerebral hemisphere), which is the lateral ventricle (first and second ventricles). This small communication on each side is the interventricular foramen. The nuclei of the thalamus and hypothalamus develop in the diencephalon. The neurohypophysis is a ventral outgrowth of the diencephalon. The cerebral cortex and basal nuclei develop in the telencephalon.

Figure 3-3 Development of brain vesicles. A, Three vesicle stages. B-F, Five vesicle stages, III, IV—ventricles.

The neural canal of the mesencephalon is reduced to a narrow tubular space called the mesencephalic aqueduct.

From the rostral rhombencephalon, the cerebellum or dorsal metencephalon develops dorsally. The remaining ventral metencephalon becomes the pons. The caudal rhombencephalon forms the myelencephalon or medulla oblongata. The fourth ventricle is the lumen of the neural canal in the rhombencephalon. It communicates with the meningeal spaces that develop around the neural tube by way of openings that arise in the wall of the neural tube caudal to the developing cerebellum. These openings are called the lateral apertures (see Figures 4-1 and 4-2). The neural canal continues caudally as the central canal of the spinal cord.

Cell Differentiation

In the first stage of development within the wall of the neural tube, the cells, which are commonly referred to as neuroepthelial or neurectodermal cells, are organized in a pseudostratified arrangement; thus the neural tube is one cell in thickness. The cell membrane of each cell spans the full width of the neural tube but the nuclei are located at various levels within each cell. These cells are all mitotically active, increasing the thickness of the wall of the tube. The nuclei migrate within the cytoplasm of each cell, and their position is dependent on the cell’s stage of mitosis.

During interphase, the nuclei are located on the external surface of the neural tube. Chromosomal DNA duplication occurs with the nucleus in that position. As the nucleus enters mitosis, it migrates through the cytoplasm to the neural canal’s luminal surface. The peripheral portion of the cytoplasm and the cell membrane also retract to the luminal position where cell division is completed. The two new daughter cells extend their cytoplasm and cell membranes back to the external surface of the neural tube. The nucleus migrates back to the periphery again. In this position, this cell can undergo another mitosis or it can differentiate. Because the nucleus is at the external surface during interphase, differentiation occurs at the external surface of the neural tube. Thus, in a short time a new layer of differentiating cells appears on the external surface of the actively dividing layer. The mitotic layer of cells is the germinal layer. The cells undergoing differentiation form the mantle layer.

The cells that are differentiated are of two types: immature neurons and spongioblasts. Immature neurons are the primary parenchymal cells of the nervous system. They are often referred to as neuroblasts but this is a misnomer because once a neuron is formed it will not divide again as the term neuroblast implies. The differentiated immature neuron grows extensively, forming long processes in becoming a mature functioning cell, but it does not divide again. Spongioblasts are the progenitors of the neurectodermal supporting cells of the nervous system, the neuroglia (glue). Two of the three forms of glial cells are derived from these spongioblasts: astrocytes and oligodendrocytes (Fig. 3-4). The third glial cell is the microglial cell, which is mesodermal in origin. It is a monocyte that enters the nervous system from its blood supply.

Figure 3-4 Mitosis and differentiation of neuroepithelial cells.

As the primitive neurons and spongioblasts are differentiated and grow and the neurons produce processes, the neural tube becomes arranged in three concentric layers (Fig. 3-5). Adjacent to the lumen of the neural tube is the germinal layer of proliferating neuroepithelial cells. This proliferative mitotic activity will ultimately be exhausted, reducing the germinal layer to a single layer of cells ranging from squamous to columnar and called ependymal cells. These ependymal cells line the entire lumen of the neural tube, which includes the ventricular system in the brain and the central canal of the spinal cord. Peripheral to this germinal layer in the embryonic neural tube is the thick layer of differentiated cells, the immature neurons, and spongioblasts. They form the mantle layer, which will ultimately become the gray matter of the definitive spinal cord, the nuclei of the brainstem, the nuclei and cortex of the cerebellum, and the basal nuclei and cerebral cortex of the telencephalon. The latter requires a migration of these neurons from the mantle layer to the external surface of the neural tube. The external layer of the neural tube is the marginal layer; it is composed primarily of the growing axonal processes of the neuronal cell bodies in the mantle layer. These axons will be myelinated by the oligodendroglial cells forming tracts in the white matter.

Figure 3-5 Functional organization of the neural tube. GP, General proprioception; GSA, general somatic afferent; GSE, general somatic efferent; GVA, general visceral afferent; GVE, general visceral efferent; SP, special proprioception; SSA, special somatic afferent; SVA, special visceral afferent.

From the mesencephalon caudally, a longitudinal groove, the sulcus limitans, appears in the lateral wall of the neural canal. Thus the neural canal can be artificially divided into dorsal and ventral portions by an imaginary dorsal plane at the level of this sulcus. The dorsal portion is called the alar plate and the ventral portion the basal plate. Functionally the alar plate mantle layer is concerned predominantly with sensory systems, and the basal plate mantle layer with motor systems (see Fig. 3-5).

MEDULLA SPINALIS: SPINAL CORD (See Fig. 2-17)

In this text, the term spinal cord is used rather than medulla spinalis, the nomenclature preferred by Nomina Anatomica Veterinaria. The spinal cord provides the best example of the symmetric development of the neural tube by layers. Ventral growth of the two basal layers and associated marginal layers beyond the level of the floor plate (Fig. 3-6) leaves a separation between the two sides, which is the ventral median fissure. The mantle and marginal layers of the alar plates grow dorsally. The dorsal marginal layers fuse on the median plane to form a dorsal median septum that may be poorly defined. The external margin of this septum forms the dorsal median sulcus. This midline growth displaces the roof plate region ventrally, resulting in a reduction of the neural canal to form the small central canal of the spinal cord lined by ependymal cells. The mantle layer of the alar plate becomes the dorsal gray column (also referred to as horn), and that of the basal plate becomes the ventral gray column. The mantle zone at the plane of the sulcus limitans becomes the intermediate gray column (see Fig. 3-6).

Figure 3-6 Development and functional organization of the spinal cord.

Not only is there a gross topographic differentiation of function of primitive neurons between the alar and basal plates, but within the mantle layer of each plate, neurons are further arranged in functional columns. The general visceral afferent and general visceral efferent neurons are located adjacent to each other in their respective gray columns on either side of the dorsal plane through the sulcus limitans. The general somatic afferent and general proprioceptive neuronal columns are located dorsally in the alar plate of the mantle layer, and the general somatic efferent column is located ventrally in the basal plate of the mantle layer. Because the relative size of the components of each spinal cord segment depends on the volume of tissue being innervated, at the levels of the limbs the spinal cord segments responsible for their innervation are enlarged forming the cervical and lumbosacral intumescences. The ultimate growth to maturity of a neuron in the peripheral nervous system depends on its appropriate innervation of a muscle cell (general somatic efferent [GSE]) or formation of a peripheral receptor (general somatic afferent [GSA], general proprioception [GP]). The lack of such innervation results in the degeneration of that neuron. In the cervical and thoracolumbar regions where appendages are not innervated, the immature primitive neurons in the basal plate mantle layer and the adjacent spinal ganglion that fail to innervate structures will degenerate by a process of cell death referred to as apoptosis. The shape of the ventral gray column depicts this process.

In the basal plate mantle layer, the GSE neurons located medially innervate the axial skeletal muscles. Those located laterally innervate the appendicular skeletal muscles. Within these areas of the ventral gray column, the GSE neuronal cell bodies can be further grouped according to the specific peripheral nerve that contains their axon and by the specific muscles innervated.

The growth of axons of the basal plate neurons through the marginal layer and outside the neural tube forms the ventral root and part of the spinal nerve and further branching of the peripheral nerves. This includes the general somatic efferent neurons located in the ventral gray column and the general visceral efferent neurons located in the intermediate gray column adjacent to the sulcus limitans. These latter general visceral efferent (GVE) neurons are the preganglionic lower motor neurons of the autonomic nervous system. This intermediate gray column is only present in the thoracic, cranial lumbar and sacral spinal cord segments. In the other segments, it was present in the embryo but subsequently degenerated due to the absence of a target organ or biochemical attractant. These GVE neurons terminate in ganglia in the peripheral nervous system that contain cell bodies of the postganglionic neurons in this two-neuron lower motor neuron system (Figs. 3-7 and 3-8; see also Fig. 3-6).

Figure 3-7 Spinal ganglia development from the neural crest.

Figure 3-8 Neural crest contribution to the development of GVE neurons.

Neural Crest

The neural crest cells are the cell bodies in the longitudinal column of cells that formed dorsolateral to the neural tube. Along the developing spinal cord segments, these cells provide the neurons that form the spinal ganglia at each segment. Adjacent to each somite a proliferation of neural crest cells forms the segmental spinal ganglion (see Figs. 3-1 and 3-7). One portion of the axon that emerges from each of these cell bodies grows centrally into the spinal cord segment to enter the alar plate dorsal gray column forming the dorsal root. The other portion of the axon grows distally to form a sensory component of the spinal nerve and further branches of the peripheral nerves. The point of penetration of the marginal white matter layer of the spinal cord segment by the axons in the dorsal and ventral roots divides the spinal cord white matter processes into three regions called funiculi. These are the dorsal, lateral, and ventral funiculi on each side of the spinal cord.

The formation of spinal ganglia is only one of many outcomes of neural crest differentiation. Prior to its segregation into spinal gangli, an early migration of cells from this neural crest column provides melanoblasts to the somitic dermatome and adjacent epidermis as well as to the cell bodies of postganglionic axons in the two-neuron GVE system.

These latter cell bodies form the ganglia of the sympathetic trunk and the abdominal plexus sympathetic ganglia as well as the medullary cells in the adrenal gland (see Fig. 3-8). These adrenal medullary cells do not grow any processes but synthesize and elaborate into the blood stream the same endocrine substance, norepinephrine, that is the neurotransmitter released at the telodendron of the sympathetic postganglionic axon derived from the neural crest cells. Although the melanoblasts and GVE neurons seem unrelated, their common denominator is the unique metabolism of tyrosine, which provides melanin for the melanocytes and the norepinephrine for the neuron. In addition, there is extensive migration of the neural crest cells into the wall of the developing gastrointestinal tract. These will form the postganglionic neurons of the parasympathetic portion of the GVE lower motor neuron as well as interneurons; and they form the glial cells that develop in the wall of the bowel, creating what is referred to as the enteric nervous system. The latter is extremely extensive and complex and presumably is entirely derived from the neural crest cells. A similar migration forms the postganglionic parasympathetic neurons for the urogenital system. In addition to these nervous system structures, the neural crest contributes to the formation of bone and cartilage in the skull and derivatives of the branchial arches; to the wall of the great vessels at the base of the heart; and to thyroid parafollicular (C) cells, odontoblasts, a portion of the leptomeninges and the lemmocytes, Schwann cells, that form the myelin of the peripheral nervous system. This is an amazing display of developmental capabilities in an initial column of cells. When a student is asked about the origin of a structure, if there is any doubt, relying on neural crest is a worthwhile consideration!

MYELENCEPHALON: MEDULLA OBLONGATA (See Figure 2-11 through 2-16)

In this text, the term medulla oblongata is shortened to medulla. The medulla is the most caudal portion of the brainstem and is continuous caudally with the spinal cord. The basic formation of the medulla involves only a slight modification of the development described for the spinal cord. The narrow middorsal roof plate of the initial neural tube (see Figs. 3-5 and 3-6) is stretched extensively instead of being obliterated by the proliferating alar plate and marginal tissue as it is in the spinal cord. Imagine grasping the midline roof plate of the neural tube with both hands and then pulling your hands apart sideways. This would stretch out a thin layer of neural tube (roof plate) and displace the entire alar and basal plates to a lateral and ventral position (Fig. 3-9). This would enlarge the lumen of the neural tube to form the fourth ventricle of the medulla, which is covered dorsally by only a single cell layer of neuroepithelial cells. At this site these cells will not enter mitosis but will remain as a single layer of ependymal cells. The sulcus limitans that is present on the ventrolateral wall of the fourth ventricle provides the plane of division of the medulla into a ventromedial basal plate and a dorsolateral alar plate, which have the same functional significance as in the spinal cord development.

Figure 3-9 Functional organization of cranial nerves VI to XII in the myelencephalon. CN VI, Abducent; CN VII, facial; CN VIII, vestibulocochlear; CN IX, glossopharyngeal; CN X, vagus; CN XI, accessory; CN XII, hypoglossal; GP, general proprioception; GSA, general somatic afferent; GSE, general somatic efferent; GVA, general visceral afferent; GVE, general visceral efferent; SP, special proprioception; SSA, special somatic afferent; SVA, special visceral afferent.

Throughout the brainstem, the mantle layer of the neural tube is broken up into nuclei that are collections of neuronal cell bodies with a common purpose, and they are interspersed with neuronal processes. Some nuclei are more distinct than others. The functional columns described in the spinal cord have a similar location in the brainstem. In addition, there are neurons in the medulla that are organized into functional groups that are present only in cranial nerves (see Fig. 3-9).

In domestic animals, cranial nerves VI through XII and the trapezoid body are part of the medulla. The rostral border of the medulla is the caudal border of the pontine transverse fibers. In the primate and some nondomesticated species, the transverse fibers of the pons expand caudally to cover the trapezoid body, so cranial nerves VI through VIII are included with V in the pons. Cranial nerves VI, VII, IX, X, XI, and XII contain general somatic efferent neurons. The medullary nuclei of cranial nerves VI and XII are located in an interrupted column along the median plane adjacent to the fourth ventricle. The hypoglossal nucleus is very long. The GSE neuronal cell bodies of the facial nerve have migrated from their initial formation in the mantle layer to form the facial nucleus in a ventrolateral position, which is closer to their common source of sensory stimuli coursing into the medulla in the spinal tract of the trigeminal nerve. This phenomenon of migration is referred to as neurobiotaxis. As a result of this migration, the axons leaving this facial nucleus initially course dorsomedially to the floor of the fourth ventricle before turning to course ventrolaterally to leave the medulla and form the facial nerve. The GSE cell bodies of cranial nerves IX, X, and XI undergo a similar migration ventrolaterally and accumulate in nucleus ambiguus, which is well named because it is a poorly defined nucleus. The preganglionic neurons of the parasympathetic portion of the GVE system are located in an interrupted column just ventromedial to the sulcus limitans, similar to their location in the spinal cord. Their axons leave the medulla in cranial nerves VII, IX, X, and XI.

The sensory components of cranial nerves associated with the medulla arise primarily from primitive neurons that develop from the column of neural crest cells, with a few arising from ectodermal cells that proliferate from branchial arch ectoderm. The latter areas are referred to as cranial placodes. These two sources form the sensory ganglia of cranial nerves VII, IX, and X, which are concerned with general visceral afferent and special visceral afferent (taste) function. Ectodermal cells derived from the otic placode form the sensory ganglia of cranial nerve VIII, which is concerned with special proprioception for vestibular system function and with the special somatic afferent system for auditory function. These cranial nerve VIII ganglia are located in the inner ear within the petrosal portion of the temporal bone. Their axons course into the alar plate region of the medulla to synapse on cell bodies comparable to the dorsal gray column cell bodies in the spinal cord (see Fig. 3-9).

The leptomeninges that surround the entire developing central nervous system (CNS; neural tube) arise from neural crest cells and adjacent mesodermal cells. These meninges contain the bulk of the blood vessels that supply the CNS and the roots of the peripheral nerves. Dorsal to the stretched-out roof plate of the fourth ventricle, the capillary blood vessels proliferate to form the two longitudinal rows of a dense capillary bed. The adjacent ependymal cells enlarge into cuboidal cells, and the entire structure (cuboidal ependymal cells, pia mater, and capillary bed) hangs down into the lumen of the fourth ventricle (Fig. 3-10). This is called the choroid plexus of the fourth ventricle. By strict definition, only the proliferated capillary bed is the plexus. Thus the choroid plexus of the fourth ventricle comprises two sagittal lines parallel to and on either side of the median plane. These extend from the caudal part of the fourth ventricle rostrally to the level of the cerebellar peduncles where each plexus turns laterally. At this point there is an opening that develops in the medullary roof plate, called the lateral aperture. This aperture allows communication between the lumen of the fourth ventricle and the subarachnoid space that develops in the leptomeninges. At the level of this lateral aperture, the choroid plexus protrudes from the lumen of the fourth ventricle out through the aperture, where it is visible on each side at the cerebellomedullary angle (see Fig. 3-10). The aperture itself is invisible grossly because it is filled with this choroid plexus. The choroid plexus is a major site of formation of cerebrospinal fluid (see Chapter 4). In domestic animals, the lateral aperture is the only communication between the ventricular system of the brain and the subarachnoid space, which makes it critical for the maintenance of normal intracranial pressure. Primates have an additional aperture located caudally in the caudal medullary velum of the fourth ventricle.

Figure 3-10 Development of the roof plate and choroid plexus of the fourth ventricle.

METENCEPHALON: CEREBELLUM AND PONS (See Figs. 2-9 and 2-10)

The initial development of the metencephalon is comparable to that of the myelencephalon. Cranial nerve V, the trigeminal nerve, is associated with this segment of the brainstem (Fig. 3-11). Its motor neurons arise in the basal plate mantle layer, migrate a short way ventrolaterally into the parenchyma of the pons, and form a small, well-defined motor nucleus. These neurons function in the general somatic efferent system and innervate the muscles of mastication derived from the somitomeres in branchial arch 1. The sensory neurons in cranial nerve V are derived primarily from neural crest cells and form the trigeminal ganglion. Most of these neurons are GSA and their dendritic zones are widely spread over the entire surface of the head and to the inner surface of the upper respiratory and digestive systems. A smaller component is composed of general proprioceptive neurons for the muscles and joints in the head region. These sensory neurons greatly outnumber the motor neurons. Therefore, when these sensory axons enter the alar plate region of the metencephalon, they spread out for a short distance rostrally and for a long distance caudally, forming the spinal tract of trigeminal nerve in the pons and medulla. These axons terminate in telodendria at synapses in the alar plate neurons, which form the sensory pontine nucleus of the trigeminal nerve in the pons and the nucleus of the spinal tract of the trigeminal nerve in the medulla. This spinal tract and nucleus extends the full length of the medulla, where caudally they meet the comparable functional neurons developing in the first cervical spinal nerves and spinal cord segment (see Fig. 3-11).

Figure 3-11 Development of the metencephalon: surface view and sagittal view of the afferent portion of cranial nerve V.

The cerebellum, or dorsal metencephalon, is formed primarily from the proliferation of the germinal epithelial cells of the alar plate, forming the rhombic lip (see Figs. 3-11 and 3-12). This growth dorsolaterally from each side overgrows the roof plate of the fourth ventricle so that the cerebellum forms part of the dorsal boundary of the fourth ventricle in the metencephalon. The development of the cerebellar cortex and nuclei are described in Chapter 13. The ventral metencephalon is the pons. A ventral migration of alar plate mantle layer neurons forms the pontine nucleus (see Fig. 3-12). The axons of these neurons cross the midline and course dorsally into the cerebellum. This forms the transverse fibers of the pons, which demarcate the ventral surface of the pons and the middle cerebellar peduncle.