The Developing Human Nervous System PDF

C H A P T E R 17 Nervous System Development of Nervous System 379 Birth Defects of Brain 403 Development of Spinal Cord 382 Development of Peripheral Nervous Development of Spinal Ganglia 384...

C H A P T E R 17 Nervous System Development of Nervous System 379 Birth Defects of Brain 403 Development of Spinal Cord 382 Development of Peripheral Nervous Development of Spinal Ganglia 384 System 412 Development of Spinal Meninges 385 Spinal Nerves 412 Positional Changes of Spinal Cord 387 Cranial Nerves 412 Myelination of Nerve Fibers 387 Development of Autonomic Nervous Development of Brain 392 System 414 Brain Flexures 392 Sympathetic Nervous System 414 Hindbrain 392 Parasympathetic Nervous System 414 Choroid Plexuses and Cerebrospinal Summary of Nervous System 414 Fluid 396 Midbrain 396 Clinically Oriented Problems 415 Forebrain 396 T he nervous system consists of three main regions: The central nervous system (CNS) consists of the brain and spinal cord and is protected by the cranium and vertebral column. The peripheral nervous system (PNS) includes the neurons outside the CNS as well as the cranial nerves and spinal nerves (and their associated ganglia), which connect the brain and spinal cord with peripheral structures. The autonomic nervous system (ANS) has parts in the CNS and PNS and consists of the neurons that innervate smooth muscle, cardiac muscle, glandular epithelium, and com- binations of these tissues. DEVELOPMENT OF NERVOUS SYSTEM The first indications of the developing nervous system appear during the third week as the neural plate and neural groove develop on the posterior aspect of the trilaminar embryo (Fig. 17-1A). The notochord and paraxial mesenchyme induce the overlying ectoderm to differentiate into the neural plate. Signaling molecules involve members of the transforming growth factor β family, Sonic hedgehog (SHH), and bone morphogenic proteins (BMPs). 379 380 THE DEVEL OP I NG HU M A N Oropharyngeal membrane Neural plate Neural plate Amnion Neural Neural Notochordal process groove fold Level of section B Wall of umbilical vesicle Primitive knot Primitive streak Notochordal plate Intraembryonic B mesoderm Cloacal membrane A Neural groove Neural crest Rostral Neural fold neuropore Neural groove Levels of sections: D Somite Notochord E Intraembryonic coelom F D Neural crest Somites Caudal neuropore C E Notochord Neural tube Surface ectoderm Neural crest Notochord Dorsal aorta Umbilical vesicle F F I G U R E 1 7 – 1 The neural plate folds to form the neural tube. A, Dorsal view shows an embryo of approximately 17 days that was exposed by removing the amnion. B, Transverse section of the embryo shows the neural plate and early development of the neural groove and neural folds. C, Dorsal view of an embryo of approximately 22 days shows that the neural folds have fused opposite the fourth to sixth somites but are spread apart at both ends. D to F, Transverse sections of the embryo at the levels shown in C illustrate formation of the neural tube and its detachment from the surface ectoderm. Some neuroectodermal cells are not included in the neural tube but remain between it and the surface ectoderm as the neural crest.  C H A P T E R 17 | N E RVOU S S Y ST EM 381 Dorsal FIGURE 1 7 – 2 Morphogens and transcription factors Epidermis specify the fate of progenitors in the ventral neural tube. A, Sonic BMPs hedgehog (SHH) is secreted by the notochord (NC) and the floor RP Dorsal plate (FP) of the neural tube in a ventral to dorsal gradient. Simi- larly, bone morphogenetic proteins (BMPs), members of the transforming growth factor-β superfamily, are secreted by the roof plate (RP) of the neural tube and the overlying epidermis in a dorsal to ventral gradient. These opposing morphogen gradi- ents determine dorsal-ventral cell fates. B, SHH concentration gradients define the ventral expression domains of class I V0 (repressed) and class II (activated) homeobox transcription factors. V1 Reciprocal negative interactions assist to establish boundaries of gene expression in the embryonic ventral spinal cord. p, Progeni- V2 tor; MN, motor neuron; V, ventral interneuron. (Modified from MN Jessel TM: Neuronal specification in the spinal cord: inductive V3 signals and transcription codes, Nat Rev Genet 1:20, 2000.) Ventral FP SHH SHH region of the fourth to sixth pairs of somites (see Fig. NC 17-1C and D). At this stage, the cranial two thirds of the A Ventral neural plate and tube as far caudal as the fourth pair of somites represent the future brain, and the caudal one third of the plate and tube represents the future spinal cord. Pax6 Fusion of the neural folds and formation of the neural p0 V0 tube begins at the fifth somite and proceeds in cranial and Dbx2 caudal directions until only small areas of the tube remain open at both ends (Fig. 17-3A and B). The lumen of the p1 V1 neural tube becomes the neural canal, which communi- cates freely with the amniotic cavity (see Fig. 17-3C). The cranial opening (rostral neuropore) closes at approxi- mately the 25th day, and the caudal neuropore closes at approximately the 27th day (see Fig. 17-3D). p2 V2 Closure of the neuropores coincides with the establish- ment of a vascular circulation for the neural tube. Syn- decan 4 (SDC4) and van gogh–like 2 (VANGL2) proteins appear to be involved with neural tube closure. The neuroprogenitor cells of the wall of the neural tube thicken to form the brain and spinal cord (Fig. 17-4). The pMN MN neural canal forms the ventricular system of the brain and the central canal of the spinal cord. Nkx2.2 Nkx6.1 p3 V3 NONCLOSURE OF NEURAL TUBE The current hypothesis is that there are multiple (possibly five) closure sites involved in the formation of the neural tube. Failure of closure of site 1 results in spina bifida Class I (Pax7, Dbx1, Dblx2, Irx3, Pax6) cystica (see Fig. 17-15). Meroencephaly (anencephaly) results from failure of closure of site 2 (see Fig. 17-13). SHH Neuronal fate Craniorachischisis results from failure of sites 2, 4, and 1 B Class II (Nkx2.2, Nkx6.1) to close. Site 3 nonfusion is rare. The neural tube defects (NTDs) are described later (see Fig. 17-17). It has been suggested that the most Formation of the neural folds, neural crest, and neural caudal region may have a fifth closure site from the tube is illustrated in Figures 17-1B to F and 17-2. second lumbar vertebra to the second sacral vertebra The neural tube differentiates into the CNS. and that closure inferior to the second sacral vertebra The neural crest gives rise to cells that form most occurs by secondary neurulation. Epidemiologic analysis of the PNS and ANS. of neonates with NTD supports the concept that there are multiple closures of the neural tube in humans. Neurulation (formation of the neural plate and neural tube) begins during the fourth week (22–23 days) in the  C H A P T E R 17 | N E RV OU S S Y STE M 381.e1 (Courtesy Dr. David Eisenstat, Manitoba Institute of Cell Biology, and Department of Human Anatomy and Cell Science, and Dr. Jeffrey T. Wigle, Department of Biochemistry and Medical Genet- ics, University of Manitoba, Winnipeg, Manitoba, Canada.) 382 THE DEVEL OP I NG HU M A N Rostral neuropore closing Neural groove Forebrain prominence Heart prominence Rostral neuropore Neural tube Omphaloenteric Somites duct Somites Connecting stalk Caudal neuropore A B Caudal neuropore Amnion Rostral neuropore Otic pit Amniotic cavity Pharyngeal arches Notochord Developing heart Neural tube Lens placode Umbilical Mesenchyme vesicle Omphaloenteric duct Neural canal Allantois Umbilical cord Upper limb bud Connecting stalk D C Caudal neuropore F I G U R E 1 7 – 3 A, Dorsal view of an embryo of approximately 23 days shows fusion of the neural folds, which forms the neural tube. B, Lateral view of an embryo of approximately 24 days shows the forebrain prominence and closing of the rostral neuropore. C, Diagrammatic sagittal section of the embryo at 23 days shows the transitory communication of the neural canal with the amniotic cavity (arrows). D, In the lateral view of an embryo of approximately 27 days, notice that the neuropores shown in B are closed. DEVELOPMENT OF SPINAL CORD Fig. 17-5D). These neuroepithelial cells constitute the ventricular zone (ependymal layer), which gives rise to all The primordial spinal cord develops from the caudal part neurons and macroglial cells (macroglia) in the spinal of the neural plate and caudal eminence. The neural tube cord (Fig. 17-6; see Fig. 17-5E). Macroglial cells are the caudal to the fourth pair of somites develops into the larger members of the neuroglial family of cells, which spinal cord (Fig. 17-5; see Figs. 17-3 and 17-4). The lateral includes astrocytes and oligodendrocytes. Soon, a mar- walls of the neural tube thicken, gradually reducing the ginal zone composed of the outer parts of the neuroepi- size of the neural canal until only a minute central canal thelial cells becomes recognizable (see Fig. 17-5E). This of the spinal cord exists at 9 to 10 weeks (see Fig. 17-5C). zone gradually becomes the white matter of the spinal Retinoic acid signaling is essential in the development of cord as axons grow into it from nerve cell bodies in the the spinal cord from early patterning to neurogenesis. spinal cord, spinal ganglia, and brain. Initially, the wall of the neural tube is composed of a Some dividing neuroepithelial cells in the ventricular thick, pseudostratified, columnar neuroepithelium (see zone differentiate into primordial neurons (neuroblasts).  C H A P T E R 17 | N E RVOU S S Y ST EM 383 Midbrain flexure Midbrain Hindbrain Optic vesicle Cervical flexure Neural tube Somite Spinal ganglion Notochord Forebrain Level of Aorta section B Peritoneal cavity Midgut A B Metencephalon Pontine flexure Mesencephalon Myelencephalon Diencephalon Optic cup Primordial spinal cord Telencephalon C F I G U R E 1 7 – 4 A, Schematic lateral view of an embryo of approximately 28 days shows the three primary brain vesicles: fore- brain, midbrain, and hindbrain. Two flexures demarcate the primary divisions of the brain. B, Transverse section of the embryo shows the neural tube that will develop into the spinal cord in this region. The spinal ganglia derived from the neural crest are also shown. C, Schematic lateral view of the central nervous system of a 6-week embryo shows the secondary brain vesicles and the pontine flexure that occurs as the brain grows rapidly. These embryonic cells form an intermediate zone (mantle migrate from the ventricular zone into the intermediate layer) between the ventricular and marginal zones. Neu- and marginal zones. Some glioblasts become astroblasts roblasts become neurons as they develop cytoplasmic and later astrocytes, whereas others become oligodendro- processes (see Fig. 17-6). blasts and eventually oligodendrocytes (see Fig. 17-6). The supporting cells of the CNS, called glioblasts (spon- When the neuroepithelial cells cease producing neuro- gioblasts), differentiate from neuroepithelial cells, mainly blasts and glioblasts, they differentiate into ependymal after neuroblast formation has ceased. The glioblasts cells, which form the ependyma (ependymal epithelium) 384 THE DEVEL OP I NG HU M A N Roof plate Dorsal median septum Neural canal Marginal zone Afferent neuroblasts Central canal Primordium of in spinal ganglion Dorsal gray horn Neural tube spinal ganglion Alar plate Ventral gray horn Sulcus limitans Motor neuron Basal plate A Ventral White Motor neuroblast Floor plate median matter B Trunk of fissure spinal nerve C Ventral motor root Internal limiting Dividing neuroepithelial cell Mesenchyme membrane Spinal External meninges limiting membrane Ventricular zone Marginal zone Neuroepithelial cells Intermediate D E (mantle) zone F I G U R E 1 7 – 5 Development of the spinal cord. A, Transverse section of the neural tube of an embryo of approximately 23 days. B and C, Similar sections at 6 and 9 weeks, respectively. D, Section of the wall of the neural tube shown in A. E, Section of the wall of the developing spinal cord shows its three zones. Notice that the neural canal of the neural tube is converted into the central canal of the spinal cord (A to C). lining the central canal of the spinal cord. SHH signal- Cell bodies in the alar plates form the dorsal gray ing controls the proliferation, survival, and patterning columns, which extend the length of the spinal cord. In of neuroepithelial progenitor cells by regulating GLI transverse sections of the cord, these columns are the transcription factors (see Fig. 17-2). dorsal gray horns (see Fig. 17-7). Neurons in these Microglia (microglial cells), which are scattered columns constitute afferent nuclei and groups of them throughout the gray and white matter of the spinal cord, form the dorsal gray columns. As the alar plates enlarge, are small cells that are derived from mesenchymal cells the dorsal median septum forms. Cell bodies in the basal (see Fig. 17-6). Microglia invade the CNS rather late in plates form the ventral and lateral gray columns. the fetal period after it has been penetrated by blood In transverse sections of the spinal cord, these columns vessels. Microglia originate in the bone marrow and are are the ventral gray horns and lateral gray horns, respec- part of the mononuclear phagocytic cell population. tively (see Fig. 17-5C). Axons of ventral horn cells grow Proliferation and differentiation of neuroepithelial out of the spinal cord and form the ventral roots of the cells in the developing spinal cord produce thick walls spinal nerves. As the basal plates enlarge, they bulge and thin roof plates and floor plates (see Fig. 17-5B). ventrally on each side of the median plane. As this occurs, Differential thickening of the lateral walls of the spinal the ventral median septum forms, and a deep longitudinal cord soon produces a shallow longitudinal groove on groove (ventral median fissure) develops on the ventral each side, the sulcus limitans (Fig. 17-7; see Fig. 17-5B). surface of the spinal cord (see Fig. 17-5C). This groove separates the dorsal part (alar plate) from the ventral part (basal plate). The alar and basal plates produce longitudinal bulges extending through most of Development of Spinal Ganglia the length of the developing spinal cord. This regional The unipolar neurons in the spinal ganglia (dorsal root separation is of fundamental importance because the alar ganglia) are derived from neural crest cells (Figs. 17-8 and and basal plates are later associated with afferent and 17-9). The axons of cells in the spinal ganglia are at first efferent functions, respectively. bipolar, but the two processes soon unite in a T-shaped  C H A P T E R 17 | N E RVOU S S Y ST EM 385 Mesenchymal cell Neuroepithelium (neuroectoderm) Neural tube Microglial cell Apolar neuroblast Glioblast (spongioblast) Ependyma Bipolar neuroblast Epithelium of choroid plexus Astroblast Oligodendroblast Unipolar neuroblast Dendrite Oligodendrocyte Protoplasmic astrocyte Fibrous astrocyte Axon Neuron F I G U R E 1 7 – 6 Histogenesis of cells in the central nervous system. After further development, the multipolar neuroblast (lower left) becomes a nerve cell or neuron. Neuroepithelial cells give rise to all neurons and macroglial cells. Microglial cells are derived from mesenchymal cells that invade the developing nervous system with the blood vessels. fashion. Both processes of spinal ganglion cells have the the neural tube (primordium of the brain and spinal cord) structural characteristics of axons, but the peripheral and form the primordial meninges (see Fig. 17-1F). process is a dendrite in that there is conduction toward The external layer of these membranes thickens to the cell body. The peripheral processes of spinal ganglion form the dura mater (Fig. 17-10A and B), and the internal cells pass in the spinal nerves to sensory endings in layer, the pia arachnoid, is composed of pia mater somatic or visceral structures (see Fig. 17-8). The central and arachnoid mater (leptomeninges). Fluid-filled spaces processes enter the spinal cord and constitute the dorsal appear within the leptomeninges that soon coalesce roots of spinal nerves. to form the subarachnoid space (see Fig. 17-12A). The origin of the pia mater and arachnoid from a single layer is indicated in the adult by arachnoid trabeculae, which Development of Spinal Meninges are numerous, delicate strands of connective tissue that The meninges (membranes covering the spinal cord) pass between the pia and arachnoid. Cerebrospinal develop from cells of the neural crest and mesenchyme fluid (CSF) begins to form during the fifth week (see between 20 and 35 days. The cells migrate to surround Fig. 17-12A). 386 THE DEVEL OP I NG HU M A N Roof plate Dorsal root of Alar plate spinal nerve F I G U R E 1 7 – 7 Transverse section of an embryo (×100) at Sulcus limitans Carnegie stage 16 at approximately 40 days. The ventral root of Central canal the spinal nerve is composed of nerve fibers arising from neuro- Neuroepithelium blasts in the basal plate (developing ventral horn of spinal cord), whereas the dorsal root is formed by nerve processes arising from Spinal ganglion Basal plate neuroblasts in the spinal ganglion. (From Moore KL, Persaud TVN, Floor plate Shiota K: Color atlas of clinical embryology, ed 2, Philadelphia, 2000, Saunders.) Developing body of vertebra Ventral root of spinal nerve Neural crest Neural crest cells Neural crest cells Neural tube Dorsal gray Spinal ganglion horn Spinal cord Dorsal root Site of Unipolar neuron lateral gray (spinal ganglion cell) horn Ventral Satellite cell gray horn Spinal nerve Schwann cell Ventral root White communicating ramus Multipolar neuron (sympathetic ganglion cell) Ganglion of sympathetic trunk Melanocyte Suprarenal medulla (chromaffin cells) Celiac Renal Suprarenal gland ganglion ganglion Plexus in intestinal tract F I G U R E 1 7 – 8 Diagram shows some derivatives (arrows) of the neural crest. Neural crest cells also differentiate into the cells in the afferent ganglia of cranial nerves and many other structures (see Chapter 5, Fig. 5-5). Formation of a spinal nerve is also illustrated.  C H A P T E R 17 | N E RVOU S S Y ST EM 387 of the first lumbar vertebra (see Fig. 17-10D). This is an Positional Changes of Spinal Cord average level because the caudal end of the spinal cord in The spinal cord in the embryo extends the entire length adults may be as superior as the 12th thoracic vertebra of the vertebral canal (see Fig. 17-10A). The spinal nerves or as inferior as the third lumbar vertebra. The spinal pass through the intervertebral foramina opposite their nerve roots, especially those of the lumbar and sacral levels of origin. Because the vertebral column and dura segments, run obliquely from the spinal cord to the cor- mater grow more rapidly than the spinal cord, this posi- responding level of the vertebral column (see Fig. 17-10D). tional relationship of the spinal nerves does not persist. The nerve roots inferior to the end of the cord (medullary The caudal end of the spinal cord in fetuses gradually cone) form a bundle of spinal nerve roots called the cauda comes to lie at relatively higher levels. In a 24-week-old equina (Latin horse tail), which arises from the lumbosa- fetus, it lies at the level of the first sacral vertebra (see cral enlargement (swelling) and medullary cone of the Fig. 17-10B). spinal cord (see Fig. 17-10D). The spinal cord in neonates terminates at the level of Although the dura mater and arachnoid mater usually the second or third lumbar vertebra (see Fig. 17-10C). In end at the S2 vertebra in adults, the pia mater does not. adults, the cord usually terminates at the inferior border Distal to the caudal end of the spinal cord, the pia mater forms a long fibrous thread, the filum terminale (terminal filum), which indicates the original level of the caudal end of the embryonic spinal cord (see Fig. 17-10C). The filum (Latin thread) extends from the medullary cone and attaches to the periosteum of the first coccygeal vertebra (see Fig. 17-10D). A B C D Neural Bipolar Unipolar crest cell neuroblasts afferent Myelination of Nerve Fibers neuron Myelin sheaths around the nerve fibers within the spinal F I G U R E 1 7 – 9 A to D, Diagrams show successive stages cord begin to form during the late fetal period and in the differentiation of a neural crest cell into a unipolar afferent continue to form during the first postnatal year (Fig. neuron in a spinal ganglion. Arrows indicate how a unipolar 17-11E). Myelin basic proteins, a family of related poly- neuron is formed. peptide isoforms, are essential in myelination; β1-integrins Body of vertebra Spinal cord Spinal cord Spinal cord Lumbosacral L1 L1 L1 L1 enlargement Dura mater Pia mater Medullary cone Intervertebral foramen Arachnoid L3 S1 Root of 1st sacral Filum terminale nerve S1 Medullary cone S1 Spinal ganglion Root of C1 1st sacral nerve S1 C1 C1 End of dural sac C1 A B C D Attachment of filum terminale F I G U R E 1 7 – 1 0 Diagrams show the position of the caudal end of the spinal cord in relation to the vertebral column and meninges at various stages of development. The increasing inclination of the root of the first sacral nerve is also illustrated. A, At 8 weeks. B, At 24 weeks. C, Neonate. D, Adult. 388 THE DEVEL OP I NG HU M A N Neurolemma Mesaxon Axon A B C D E Axon Oligodendrocyte F G H F I G U R E 1 7 – 1 1 Diagrammatic sketches illustrate myelination of nerve fibers. A to E, Successive stages in the myelination of an axon of a peripheral nerve fiber by the neurilemma (sheath of Schwann). The axon first indents the cell, and the cell then rotates around the axon as the mesaxon (site of invagination) elongates. The cytoplasm between the layers of the cell membrane gradually condenses. Cytoplasm remains on the inside of the sheath between the myelin and the axon. F to H, Successive stages in the myelina- tion of a nerve fiber in the central nervous system by an oligodendrocyte. A process of the neuroglial cell wraps itself around an axon, and the intervening layers of cytoplasm move to the body of the cell. regulate this process. Fiber tracts become functional at neurilemma (sheath of Schwann cells), which are analo- approximately the time they become myelinated. Motor gous to oligodendrocytes. Neurilemma cells are derived roots are myelinated before sensory roots. The myelin from neural crest cells that migrate peripherally and wrap sheaths around the nerve fibers in the spinal cord are themselves around the axons of somatic motor neurons formed by oligodendrocytes (oligodendroglial cells) are and preganglionic autonomic motor neurons as they pass types of glial cells that originate from the neuroepithe- out of the CNS (see Figs. 17-8 and 17-11A to E). These lium. The plasma membranes of these cells wrap around cells also wrap themselves around the central and periph- the axon, forming several layers (see Fig. 17-11F to H). eral processes of somatic and visceral sensory neurons Profilin 1 (PFN1) protein is essential in the microfilament and around the axons of postsynaptic autonomic motor polymerization that promotes changes to the oligoden- neurons. Beginning at approximately 20 weeks, periph- drocyte cytoskeleton. eral nerve fibers have a whitish appearance resulting from The myelin sheaths around the axons of peripheral the deposition of myelin (layers of lipid and protein nerve fibers are formed by the plasma membranes of the substances). BIRTH DEFECTS OF SPINAL CORD DERMAL SINUS Most defects result from failure of fusion of one or more A dermal sinus is lined with epidermis and skin append- neural arches of the developing vertebrae during the ages extending from the skin to a deeper-lying structure, fourth week. NTDs affect the tissues overlying the spinal usually the spinal cord. The sinus (channel) is associated cord: meninges, neural arches, muscles, and skin (Fig. with closure of the neural tube and formation of the 17-12). Defects involving the embryonic neural arches meninges in the lumbosacral region of the spinal cord. are referred to as spina bifida; subtypes of this defect are The birth defect is caused by failure of the surface ecto- based on the degree and pattern of the NTD. The term derm (future skin) to detach from the neuroectoderm and spina bifida denotes nonfusion of the halves of the meninges that envelop it. As a result, the meninges are embryonic neural arches, which is common to all types continuous with a narrow channel that extends to a of spina bifida (see Fig. 17-12A). Severe defects also dimple in the skin of the sacral region of the back (see involve the spinal cord, meninges, and neurocranium Fig. 17-13). The dimple indicates the region of closure of (bones of cranium enclosing the brain) (Fig. 17-13). Spina the caudal neuropore at the end of the fourth week and bifida ranges from clinically significant types to minor therefore represents the last place of separation between defects that are functionally unimportant (Fig. 17-14). the surface ectoderm and the neural tube.  C H A P T E R 17 | N E RV OU S S Y STE M 389 Unfused neural Tuft of hair arch Dura mater Skin Subarachnoid space (containing CSF) Spinal cord Back muscles Vertebra A B Membranous sac Dura mater Open spinal cord Displaced spinal cord Skin Roots of spinal nerve Subarachnoid space Spinal ganglion C D F I G U R E 1 7 – 1 2 Diagrammatic sketches illustrate various types of spina bifida and the associated defects of the vertebral arches (one or more), spinal cord, and meninges. A, Spina bifida occulta. Observe the unfused neural arch. B, Spina bifida with meningocele. C, Spina bifida with meningomyelocele. D, Spina bifida with myeloschisis. The defects illustrated in B to D are referred to collectively as spina bifida cystica because of the cyst-like sac or cyst associated with them. CSF, Cerebrospinal fluid. F I G U R E 1 7 – 1 3 A fetus at 20 weeks with severe neural tube defects, including acrania, cerebral regression (meroencephaly), iniencephaly (enlarge- ment of foramen magnum), and a sacral dimple (arrow).  C H A P T E R 17 | N E RV OU S S Y STE M 389.e1 (Courtesy Dr. Marc Del Bigio, Department of Pathology [Neuro- pathology], University of Manitoba, Winnipeg, Manitoba, Canada.) 390 THE DEVEL OP I NG HU M A N SPINA BIFIDA CYSTICA Severe types of spina bifida, which involve protrusion of the spinal cord and/or meninges through defects in the vertebral arches, are referred to collectively as spina bifida cystica because of the meningeal cyst (sac-like structure) that is associated with these defects (Fig. 17-15; see Fig. 17-12B to D). This NTD occurs in approximately 1 of 5000 births and shows considerable geographic variation in incidence. When the cyst contains meninges and CSF, the defect is spinal bifida with meningocele (see Fig. 17-12B). The spinal cord and spinal roots are in the normal position, but there may be spinal cord defects. Protrusion of the meninges and CSF of the spinal cord occurs through a defect in the vertebral column. If the spinal cord or nerve roots are contained within the meningeal cyst, the defect is spina bifida with menin- gomyelocele (see Figs. 17-12C and 17-15A). Severe cases involving several vertebrae are associated with absence of the calvaria (skullcap), absence of most of the brain, and facial abnormalities; these severe defects are called meroencephaly (see Figs. 17-13 and 17-17). The defects entail drastic effects in some brain areas and lesser or no effects in others. For these neonates, death is inevitable. The term anencephaly for these severe defects is inappropriate because it indicates that no part of the brain exists. Spina bifida cystica shows various degrees of neuro- logic deficit, depending on the position and extent of the lesion. Dermatomal loss of sensation along with com- plete or partial skeletal muscle paralysis occurs with the F I G U R E 1 7 – 1 4 A female child with a tuft of hair in the lesion (see Fig. 17-15B). The level of the lesion deter- lumbosacral region indicating the site of a spina bifida occulta. mines the area of anesthesia (area of skin without sensa- tion) and the muscles affected. Sphincter paralysis (bladder or anal sphincters) is common with lumbosacral meningomyelocele (see Figs. 17-12C and 17-15A). A saddle block anesthesia typically occurs when the sphinc- ters are involved; loss of sensation occurs in the body region that would contact a saddle. Meroencephaly is strongly suspected in utero when SPINA BIFIDA OCCULTA there is a high level of alpha fetoprotein (AFP) in the Spina bifida occulta is an NTD resulting from failure of amniotic fluid (see Chapter 6, box titled “Alpha- the halves of one or more neural arches to fuse in the Fetoprotein and Fetal Anomalies”). The level of AFP may median plane (see Fig. 17-12A). This NTD occurs in the also be elevated in maternal blood serum. Amniocentesis L5 or S1 vertebra in approximately 10% of otherwise is usually performed on pregnant women with high levels normal people. In the minor form, the only evidence of of serum AFP for the determination of the AFP level in its presence may be a small dimple with a tuft of hair the amniotic fluid (see Chapter 6, Fig. 6-13). An ultra- arising from it (see Figs. 17-12A and 17-14). An overlying sound scan may reveal an NTD that has resulted in spina lipoma dermal sinus or other birthmark may also occur. bifida cystica. The fetal vertebral column can be detected Spina bifida occulta usually produces no symptoms. A by ultrasound at 10 to 12 weeks, and if there is a defect few affected infants have functionally significant defects in the vertebral arch, a meningeal cyst may be detected of the underlying spinal cord and dorsal roots. in the affected area (see Figs. 17-12C and 17-15A).  C H A P T E R 17 | N E RV OU S S Y STE M 390.e1 (Courtesy A. E. Chudley, MD, Section of Genetics and Metabo- lism, Department of Pediatrics and Child Health, Children’s Hos- pital and University of Manitoba, Winnipeg, Manitoba, Canada.)  C H A P T E R 17 | N E RVOU S S Y ST EM 391 FIGURE 1 7 – 1 5 Infants with spina bifida cystica. A, Spina bifida with meningomyelocele in the lumbar region. B, Spina bifida with myeloschisis in the lumbar region. Notice that the nerve involvement has affected the lower limbs of the infant. A B MENINGOMYELOCELE Meningomyelocele is a more common and a more severe defect than spina bifida with meningocele (see Figs. 17-15A and 17-12B). This NTD may occur anywhere along the vertebral column; however, they are most common in the lumbar and sacral region (see Fig. 17-17). More than 90% of cases have associated hydrocephalus due to coexistence of an Arnold-Chiari malformation. Most patients require surgical diversion of CSF to avoid high intracranial pressure–related complications. Some cases of meningomyelocele are associated with cranio- lacunia (defective development of the calvaria), which results in depressed, nonossified areas on the inner sur- faces of the flat bones of the calvaria. MYELOSCHISIS FIGURE 1 7 – 1 6 A 19-week female fetus showing an Myeloschisis is the most severe type of spina bifida (Fig. open spinal defect in the lumbosacral region (spina bifida with 17-16; see Figs. 17-12D and 17-15B). In this defect, the myeloschisis). spinal cord in the affected area is open because the neural folds failed to fuse. As a result, the spinal cord is represented by a flattened mass of nervous tissue. Myeloschisis usually results in permanent paralysis or weakness of the lower limbs.  C H A P T E R 17 | N E RV OU S S Y STE M 391.e1 (Courtesy the late Dr. Dwight Parkinson, Department of Surgery (Courtesy Dr. Joseph R. Siebert, Children’s Hospital and Regional and Department of Human Anatomy and Cell Science, University Medical Center, Seattle, WA.) of Manitoba, Winnipeg, Manitoba, Canada.)  392 THE DEVEL OP I NG HU M A N midbrain and forebrain, and the alar and basal plates are recognizable only in the midbrain and hindbrain (see CAUSES OF NEURAL TUBE DEFECTS Figs. 17-5C and 17-19C). Nutritional and environmental factors undoubtedly play a role in the production of NTDs. Gene-gene and gene- Hindbrain environment interactions are likely involved in most cases. Food fortification with folic acid and folic acid The cervical flexure demarcates the hindbrain from the supplements taken before conception and continued for spinal cord (see Fig. 17-19A). Later, this junction is arbi- at least 3 months during pregnancy reduce the incidence trarily defined as the level of the superior rootlet of of NTDs. In 2015, the Centers for Disease Control and the first cervical nerve, which is located roughly at the Prevention urged “all women of childbearing age who foramen magnum. The pontine flexure, located in the future pontine region, divides the hindbrain into caudal can become pregnant to get 0.4 mg of folic acid every (myelencephalon) and rostral (metencephalon) parts. day to help reduce the risk of neural tube defects” (for The myelencephalon becomes the medulla oblongata more information, go to http://www.cdc.gov/folicacid). (commonly called the medulla), and the metencephalon Epidemiologic studies have also shown that low maternal becomes the pons and cerebellum. The cavity of the hind- B12 levels may significantly increase the risk of NTDs. brain becomes the fourth ventricle and the central canal Certain drugs (e.g., valproic acid) increase the risk of in the medulla (see Fig. 17-19B and C). meningomyelocele. This anticonvulsant drug causes NTDs in 1% to 2% of pregnancies if taken during early Myelencephalon pregnancy, when the neural folds are fusing (Fig. 17-17). The caudal part of the myelencephalon (closed part of the medulla) resembles the spinal cord developmentally and structurally (see Fig. 17-19B). The neural canal of the neural tube forms the small central canal of the myel- encephalon. Unlike those of the spinal cord, neuroblasts DEVELOPMENT OF BRAIN from the alar plates in the myelencephalon migrate into the marginal zone and form isolated areas of gray matter: 16 The brain begins to develop during the third week, when the gracile nuclei medially and the cuneate nuclei laterally the neural plate and tube are developing from the neuro- (see Fig. 17-19B). These nuclei are associated with cor- ectoderm (see Fig. 17-1). The neural tube, cranial to the respondingly named nerve tracts that enter the medulla fourth pair of somites, develops into the brain. Neuro- from the spinal cord. The ventral area of the medulla progenitor cells proliferate, migrate, and differentiate to contains a pair of fiber bundles (pyramids) that consist form specific areas of the brain. Fusion of the neural folds of corticospinal fibers descending from the developing in the cranial region and closure of the rostral neuropore cerebral cortex (see Fig. 17-19B). form three primary brain vesicles from which the brain The rostral part of the myelencephalon (open part develops (Fig. 17-18): of the medulla) is wide and rather flat, especially opposite the pontine flexure (see Fig. 17-19C and D). The pontine Forebrain (prosencephalon) flexure causes the lateral walls of the medulla to move Midbrain (mesencephalon) laterally like the pages of an open book. As a result, its Hindbrain (rhombencephalon) roof plate is stretched and greatly thinned (see Fig. During the fifth week, the forebrain partly divides into 17-19C). The cavity of this part of the myelencephalon two secondary brain vesicles, the telencephalon and dien- (part of the future fourth ventricle) becomes somewhat cephalon; the midbrain does not divide. The hindbrain rhomboidal (diamond shaped). As the walls of the partly divides into two vesicles, the metencephalon and medulla move laterally, the alar plates become lateral to myelencephalon. Consequently, there are five secondary the basal plates. As the positions of the plates change, the brain vesicles. motor nuclei usually develop medial to the sensory nuclei (see Fig. 17-19C). Neuroblasts in the basal plates of the medulla, like Brain Flexures those in the spinal cord, develop into motor neurons. The During the fifth week, the embryonic brain grows rapidly neuroblasts form nuclei (groups of nerve cells) and orga- 16 and bends ventrally with the head fold. The bending nize into three cell columns on each side (see Fig. 17-19D). produces the midbrain flexure in the midbrain region and From medial to lateral, the columns are named as follows: the cervical flexure at the junction of the hindbrain and General somatic efferent, represented by neurons of spinal cord (Fig. 17-19A). Later, unequal growth of the the hypoglossal nerve brain between these flexures produces the pontine flexure Special visceral efferent, represented by neurons inner- in the opposite direction. This flexure results in thinning vating muscles derived from the pharyngeal arches (see of the roof of the hindbrain (see Fig. 17-19C). Chapter 9, Fig. 9-6) Initially, the primordial brain has the same basic struc- General visceral efferent, represented by some ture as the developing spinal cord; however, the brain neurons of the vagus and glossopharyngeal nerves (see flexures produce considerable variation in the outline Chapter 9, Fig. 9-6) of transverse sections at different levels of the brain and in the position of the gray and white matter. The Neuroblasts in the alar plates of the medulla form sulcus limitans extends cranially to the junction of the neurons that are arranged in four columns on each side.  C H A P T E R 17 | N E RV OU S S Y STE M 393 Neural tube Neural fold Rostral neuropore Caudal neuropore Somite Defective closure of Defective closure of rostral neuropore caudal neuropore 1. Incomplete development Neural groove of brain with degeneration Neural fold 2. Incomplete development of calvaria 3. Alteration in facies (facial appearance) +/– auricle Mass of brain tissue Neural deficit Unfused vertebral caudal to lesion Meningomyelocele arch Meroencephaly +/– Clubfoot +/– Hydrocephalus Spina bifida occulta Tuft of hair Dura mater Skin Subarachnoid space Incomplete vertebral arch Myeloschisis Spinal cord Vertebra Clubfoot F I G U R E 1 7 – 1 7 Schematic illustration shows the embryologic basis of neural tube defects. Meroencephaly (partial absence of brain) results from defective closure of the rostral neuropore, and meningomyelocele results from defective closure of the caudal neuropore. (Modified from Jones KL: Smith’s recognizable patterns of human malformations, ed 4, Philadelphia, 1988, Saunders.) 394 THE DEVEL OP I NG HU M A N 3 Primary 5 Secondary Adult derivatives vesicles vesicles of Walls Cavities Wall Cavity Cerebral Lateral ventricles Telencephalon hemispheres Forebrain (prosencephalon) Thalami, etc. Third ventricle Diencephalon Midbrain Aqueduct Midbrain Mesencephalon (mesencephalon) Pons Upper part of fourth ventricle Metencephalon Cerebellum Hindbrain (rhombencephalon) Medulla Lower part of fourth ventricle Myelencephalon Spinal cord F I G U R E 1 7 – 1 8 Diagrammatic sketches of the brain vesicles indicate the adult derivatives of their walls and cavities. The rostral part of the third ventricle forms from the cavity of the telencephalon. Most of this ventricle is derived from the cavity of the diencephalon. Cerebellum Pontine flexure Central canal Gracile nucleus Hindbrain Level of section B Cuneate nucleus Central gray matter Blood vessel Midbrain flexure Spinal cord Pyramids Cervical flexure A B (composed of corticospinal fibers) Roof plate Sulcus limitans Ependymal roof Tela choroidea Choroid plexus Special somatic afferent Fourth ventricle General somatic afferent General visceral Special visceral afferent efferent General visceral afferent Special visceral efferent Alar plate Basal plate Olivary nucleus C D General somatic efferent F I G U R E 1 7 – 1 9 A, Sketch of the developing brain at the end of the fifth week of gestation shows the three primary divisions of the brain and brain flexures. B, Transverse section of the caudal part of the myelencephalon (developing closed part of medulla). C and D, Similar sections of the rostral part of the myelencephalon (developing open part of medulla) show the position and succes- sive stages of differentiation of the alar and basal plates. The arrows in C show the pathway taken by neuroblasts from the alar plates to form the olivary nuclei.  C H A P T E R 17 | N E RVOU S S Y ST EM 395 From medial to lateral, the columns are designated as in each basal plate develop into motor nuclei and orga- follows: nize into three columns on each side. The cerebellum develops from thickenings of dorsal General visceral afferent, which receives impulses from parts of the alar plates. Initially, the cerebellar swellings the viscera project into the fourth ventricle (see Fig. 17-20B). As the Special visceral afferent, which receives taste fibers swellings enlarge and fuse in the median plane, they over- General somatic afferent, which receives impulses grow the rostral half of the fourth ventricle and overlap from the surface of the head the pons and medulla (see Fig. 17-20D). Special somatic afferent, which receives impulses from Some neuroblasts in the intermediate zone of the alar the ear plates migrate to the marginal zone and differentiate into Some neuroblasts from the alar plates migrate ven- the neurons of the cerebellar cortex. Other neuroblasts trally and form the neurons in the olivary nuclei (see from these plates give rise to the central nuclei, the largest Fig. 17-19C and D). of which is the dentate nucleus (see Fig. 17-20D). Cells from the alar plates also give rise to the pontine nuclei, Metencephalon cochlear and vestibular nuclei, and the sensory nuclei of The walls of the metencephalon form the pons and cer- the trigeminal nerve. ebellum, and the cavity of the metencephalon forms the The structure of the cerebellum reflects its phylogenetic superior part of the fourth ventricle (Fig. 17-20A). As in (evolutionary) development (see Fig. 17-20C and D): the rostral part of the myelencephalon, the pontine flexure causes divergence of the lateral walls of the pons, which The archicerebellum (flocculonodular lobe), the oldest spreads the gray matter in the floor of the fourth ventricle part phylogenetically, has connections with the ves- (see Fig. 17-20B). As in the myelencephalon, neuroblasts tibular apparatus, especially the vestibule of the ear. Ependymal roof Level of section B Pia mater Cerebellar swelling (primordium of cerebellum) Developing cerebellum Somatic afferent General visceral afferent Fourth ventricle General visceral efferent Special visceral efferent Pontine nucleus General somatic efferent Developing pons and medulla A B Primary fissure Capillary Cerebellar Developing anterior Anterior lobe cortex Midbrain lobe of cerebellum (paleocerebellum) Posterior lobe Nodule (neocerebellum) Choroid plexus Cerebral Flocculonodular lobe aqueduct (archicerebellum) Tela choroidea Dentate nucleus Fourth ventricle C Pons Medulla D Pons Choroid plexus Medulla F I G U R E 1 7 – 2 0 A, Sketch of the developing brain at the end of the fifth week. B, Transverse section of the metencephalon (developing pons and cerebellum) shows the derivatives of the alar and basal plates. C and D, Sagittal sections of the hindbrain at 6 and 17 weeks, respectively, show successive stages in the development of the pons and cerebellum.  396 THE DEVEL OP I NG HU M A N The paleocerebellum (vermis and anterior lobe), of Neuroblasts (Greek blastos, germ) are embryonic more recent development, is associated with sensory nerve cells that migrate from the alar plates of the mid- data from the limbs. brain into the tectum (roof-like covering) and aggregate The neocerebellum (posterior lobe), the newest part to form four large groups of neurons, the paired superior phylogenetically, is concerned with selective control of and inferior colliculi (see Fig. 17-21C to E), which are limb movements. concerned with visual and auditory reflexes, respectively. Neuroblasts from the basal plates may give rise to groups Nerve fibers connecting the cerebral and cerebellar of neurons in the tegmentum of the midbrain (red nuclei, cortices with the spinal cord pass through the marginal nuclei of third and fourth cranial nerves, and reticular layer of the ventral region of the metencephalon. This nuclei). The substantia nigra, a broad layer of gray matter region of the brainstem is the pons (Latin bridge) because adjacent to the crus cerebri (cerebral peduncles) may also of the robust band of nerve fibers that crosses the median differentiate from the basal plate (see Fig. 17-21B, D, plane and forms a bulky ridge on its anterior and lateral and E); however, some authorities think the substantia aspects (see Fig. 17-20C and D). nigra is derived from cells in the alar plate that migrate ventrally. Choroid Plexuses and Fibers growing from the cerebrum (principal part of brain, including the diencephalon and cerebral hemi- 16 Cerebrospinal Fluid spheres) form the crus cerebri (cerebral peduncles) The thin ependymal roof of the fourth ventricle is covered anteriorly (see Fig. 17-21B). The peduncles become pro- externally by pia mater, which is derived from mesen- gressively more prominent as more descending fiber chyme associated with the hindbrain (see Fig. 17-20B to groups (corticopontine, corticobulbar, and corticospinal) D). This vascular membrane, together with the ependy- pass through the developing midbrain on their way to the mal roof, forms the tela choroidea, the sheet of pia cover- brainstem (the medulla is the caudal subdivision of the ing the lower part of the fourth ventricle (see Fig. 17-19D). brainstem that is continuous with the spinal cord) and Because of the active proliferation of the pia, the tela spinal cord (see Fig. 17-21C). choroidea invaginates the fourth ventricle, where it dif- ferentiates into the choroid plexus, infoldings of choroi- dal arteries of the pia (see Figs. 17-19C and D and 17-20C Forebrain and D). Similar plexuses develop in the roof of the third As closure of the rostral neuropore occurs (see Fig. ventricle and the medial walls of the lateral ventricles. 17-3B), two lateral outgrowths (optic vesicles) appear The choroid plexuses secrete ventricular fluid, which (see Fig. 17-4A), one on each side of the forebrain. becomes CSF as additions are made to it from the sur- These vesicles are the primordia of the retinae and faces of the brain, spinal cord, and the pia-arachnoid optic nerves (see Chapter 18, Figs. 18-1C, F, and H and layer of the meninges. Various signaling morphogens 18-11). A second pair of diverticula, the telencephalic are found in CSF and the choroid plexus that are vesicles, soon arise more dorsally and rostrally (see Fig. necessary for brain development. The thin roof of the 17-21C). They are the primordia of the cerebral hemi- fourth ventricle evaginates in three locations. These out- spheres, and their cavities become the lateral ventricles pouchings rupture to form openings, the median and (see Fig. 17-26B). lateral apertures (foramen of Magendie and foramina of The rostral (anterior) part of the forebrain, including Luschka, respectively), which permit the CSF to enter the the primordia of the cerebral hemispheres, is the telen- subarachnoid space from the fourth ventricle. Specific cephalon; the caudal (posterior) part of the forebrain is neurogenic molecules (e.g., retinoic acid) control the the diencephalon. The cavities of the telencephalon and proliferation and differentiation of neuroprogenitor diencephalon contribute to the formation of the third cells. The epithelial lining of the choroid plexus is derived ventricle, although the cavity of the diencephalon con- from neuroepithelium, whereas the stroma develops from tributes more (Fig. 17-22E). mesenchymal cells. The main site of absorption of CSF into the venous Diencephalon system is through the arachnoid villi, which are protru- Three swellings develop in the lateral walls of the third sions of arachnoid mater into the dural venous sinuses ventricle, which later become the thalamus, hypothala- (large venous channels between the layers of the dura mus, and epithalamus (see Fig. 17-22C to E). The thala- mater). The arachnoid villi consist of a thin cellular layer mus is separated from the epithalamus by the epithalamic derived from the epithelium of the arachnoid and the sulcus and from the hypothalamus by the hypothalamic endothelium of the sinus. sulcus (see Fig. 17-22E). The latter sulcus is not a con- tinuation of the sulcus limitans into the forebrain, and it does not, like the sulcus limitans, divide sensory and Midbrain motor areas (see Fig. 17-22C). The midbrain (mesencephalon) undergoes less change The thalamus (large, ovoid mass of gray matter) devel- than other parts of the developing brain (Fig. 17-21A), ops rapidly on each side of the third ventricle and bulges except for the caudal part of the hindbrain. The neural into its cavity (see Fig. 17-22E). The thalami meet and canal narrows and becomes the cerebral aqueduct (see fuse in the midline in approximately 70% of brains, Figs. 17-20D and 17-21D), a channel that connects the forming a bridge of gray matter across the third ventricle, third and fourth ventricles. which is the interthalamic adhesion (variable connection  C H A P T E R 17 | N E RVOU S S Y ST EM 397 Primordia of colliculi Level of section B Midbrain Hindbrain Substantia nigra Crus cerebri B (cerebral peduncle) A Mesencephalic nucleus (CN V) Inferior colliculus Cerebral aqueduct Trochlear nucleus Telencephalic vesicle (somatic efferent) (primordial cerebral hemisphere) Decussation of superior cerebellar peduncle Substantia nigra Levels of sections E D Interpeduncular fossa Crus cerebri D Inferior colliculus Superior colliculus Mesencephalic Cerebellum nucleus (CN V) Oculomotor nucleus (CN III) Red nucleus Crus cerebri C Pons Medulla Substantia nigra E F I G U R E 1 7 – 2 1 A, Sketch of the developing brain at the end of the fifth week. B, Transverse section of the developing midbrain shows the early migration of cells from the basal and alar plates. C, Sketch of the developing brain at 11 weeks. D and E, Transverse sections of the developing midbrain at the level of the inferior and superior colliculi, respectively. between the two thalamic masses across the third ven- pathway has been implicated in the proliferation and dif- tricle); the bridge is absent in about 20% of brains. ferentiation of pituitary progenitor cells. The pituitary The hypothalamus arises by proliferation of neuro- develops from two sources: blasts in the intermediate zone of the diencephalic walls, An upgrowth from the ectodermal roof of the stomo- ventral to the hypothalamic sulci (see Fig. 17-22E). Dif- deum, the hypophyseal diverticulum (Rathke pouch) ferential expression of Wnt/β-catenin signaling is involved A downgrowth from the neuroectoderm of the dien- in the patterning of the hypothalamus. Later, a number cephalon, the neurohypophyseal diverticulum of nuclei concerned with endocrine activities and homeo- stasis develop. A pair of nuclei forms pea-sized swellings This double origin explains why the pituitary gland is (mammillary bodies) on the ventral surface of the hypo- composed of two different types of tissue: thalamus (see Fig. 17-22C). The adenohypophysis (glandular tissue), or anterior The epithalamus develops from the roof and dorsal lobe, arises from oral ectoderm portion of the lateral wall of the diencephalons (see Fig. The neurohypophysis (nervous tissue), or posterior 17-22C to E). Initially, the epithalamic swellings are lobe, arises from neuroectoderm large, but later they become relatively small. The pineal gland (pineal body) develops as a median By the third week, the hypophyseal diverticulum proj- diverticulum of the caudal part of the roof of the dien- ects from the roof of the stomodeum and lies adjacent to cephalon (see Fig. 17-22D). Proliferation of cells in its the floor (ventral wall) of the diencephalon (see Fig. walls soon converts it into a solid, cone-shaped gland. 17-23C). By the fifth week, the diverticulum has elon- The pituitary gland (hypophysis) is ectodermal in gated and constricted at its attachment to the oral epithe- origin (Fig. 17-23 and Table 17-1). The Notch signaling lium. By this stage, it has come into contact with the 398 THE DEVEL OP I NG HU M A N Midbrain Cerebellum Hindbrain Cerebral hemisphere Forebrain Optic cup A B Olfactory bulb Optic nerve Epithalamus Mesencephalon Pineal gland Cerebral hemisphere Thalamus Epithalamus Alar plate Cerebellum Sulcus limitans Basal plate Cerebellum Thalamus Hypothalamus Mammillary body Optic chiasma Level of section E Hypothalamus Infundibulum D Infundibulum C Optic chiasm Ependymal roof Epithalamus Epithalamic sulcus Third Thalamus ventricle Hypothalamic sulcus Hypothalamus E F I G U R E 1 7 – 2 2 A, Sketch shows an external view of the brain at the end of the fifth week. B, Similar view at 7 weeks. C, Median section of the brain at 7 weeks shows the medial surface of the forebrain and midbrain. D, Similar section at 8 weeks. E, Transverse section of the diencephalon shows the epithalamus dorsally, the thalamus laterally, and the hypothalamus ventrally. infundibulum (derived from the neurohypophyseal diver- extension, the pars tuberalis, grows around the infun- ticulum), a ventral downgrowth of the diencephalon (see dibular stem (see Fig. 17-23E). The extensive prolifera- Figs. 17-22C and D and 17-23). tion of the anterior wall of the hypophyseal diverticulum The stalk of the hypophyseal diverticulum passes reduces its lumen to a narrow cleft (see Fig. 17-23E). The between the chondrification centers of the developing residual cleft is usually not recognizable in the adult presphenoid and basisphenoid bones of the cr