Compare the marginal layer of the neural tube to the mantle layer.
Describe the neural crest derivatives that may be associated with the somatic sensory nervous system; the derivatives associated with the autonomic nervous system; and the derivatives associated with the adrenal gland and skin.
Describe the adult derivatives of the secondary vesicles.
Compare the function and location of the alar and basal plate in the spinal cord.
Explain the potential outcome that results from a failure of neural crest cells to migrate.
Explain the potential outcome that results from a failure of neuroblasts to migrate from the ventricular zone during cortical development.
Overview of Nervous System Development
Introduction
Development of the central and peripheral nervous system begins in the third week of embryonic development due to inductive signals originating from the notochord (axial mesoderm). Signaling molecules secreted from the notochord induces a portion of the overlying ectoderm to differentiate into neuroectoderm and form the neural plate. This is followed by neurulation which is the process by which the neural plate folds inward and then fuses to form the neural tube. The central nervous system differentiates from the neural tube, whereas the peripheral nervous system develops from neural crest cells that originate from the dorsal margin of the neural tube. Failure for neurulation to occur properly leads to several pathological conditions that may impact fetal development.
Neural Tube Development
Primary and Secondary Neurulation
Differential growth of the neural plate results in upward growth and inward folding of the lateral edges of the neural plate to form the neural folds. The center of the neural plate invaginates downward, forming the neural groove (a, b).
During neurulation, the dorsal margins of the neural folds begin to fuse in the midline, converting the neural groove into the neural tube. As the neural folds begin to fuse, neural crest cells separate from the free edge and migrate away from the neural tube (c, d).
The neural tube continues to fuse along the craniocaudal axis and becomes separated from the surface ectoderm. Two openings, known as anterior and posterior neuropores, initially remain open on the cranial (rostral) and caudal ends of the fused neural tube and then close during the fourth week. Failure of the neural tube to fuse properly leads to neural tube defects.
The expanded cranial portion of the neural tube gives rise to the brain and the caudal portion gives rise to the spinal cord. The lumen of the tube, known as the neural canal, persists and develops into the ventricles of the brain and central canal of the spinal cord.
In the caudal end of the neural tube, a solid cell mass known as the conus medullaris appears on day 20. The conus medullaris forms a central cavity and then fuses with the terminal end of the neural tube to form the distal portion of the spinal cord in a process known as secondary neurulation.
Fig. 2.1 (a–d) Process of neurulation. Schematic diagram demonstrating the stages of neurulation leading to the development of the central (CNS) and peripheral nervous system (PNS). Dorsal view of embryo (a,c); cross-section of embryo (b,d). The neural tube develops from the neural plate on the dorsal surface of the embryo. A central groove initially develops in the neural plate forming the neural groove. Neural crest cells migrate from the free edge of the groove as the neural groove fuses together, and the closed neural tube separates from the overlying ectoderm. The brain and spinal cord differentiate from the neural tube, whereas neural structures associated with PNS develop from neural crest cells.
Neural tube defects occur when various parts of the neural tube fail to fuse.
Anencephaly is a lethal condition in which a significant portion of the brain and skull fail to develop. It results from a failure of the anterior neuropore to fuse.
A persistent opening in the posterior neuropore causes spina bifida. The severity depends on the length and position of the defect. Severe forms, such as spina bifida cystica, are associated with neurological defects and herniation of the spinal cord through the vertebral arches due to the incomplete development of the spinal cord, meninges, and vertebrae.
Tethered cord syndrome is a disorder associated with the tethering (fixation) of the caudal spinal cord tissue that results in limited movement of the spinal cord within the vertebral column. Clinical presentations include, but are not limited to, gait abnormalities, foot and spinal deformities, and urinary tract issues.
Neural Crest Formation and Migration
Neural crest cells develop from the dorsal surface of the neural folds and detach as the neural tube starts to fuse. Neural crest cells migrate away from the neural tube along specific routes and populate the developing head, heart, and trunk, where they differentiate into a variety of structures ().
Defects in neural crest migration lead to a variety of developmental disorders including craniofacial abnormalities.
Neural crest cells move cranially toward the head and neck and contribute to neurons of the cranial sensory ganglia and autonomic ganglia of the peripheral nervous system.
The two inner meningeal layers collectively referred to as the leptomeninges, consisting of arachnoid and pia, are also derived from cranial neural crest cells.
In addition, cranial neural crest cells combine with mesenchyme in developing pharyngeal arch region to form neural crest–derived ectomesenchyme. Ectomesenchyme forms the connective tissue and skeletal derivatives of the head and neck, including the dentin and cementum of the teeth.
Neural crest cells migrate toward the cardiac region to aid in the development and septation of the heart and great vessels.
Neural crest cells migrate caudally to the trunk (body) and give rise to neurons of the peripheral spinal sensory ganglia (dorsal root ganglia), enteric ganglia of the gastrointestinal tract, autonomic ganglia of the autonomic nervous system, and chromaffin cells of the adrenal medulla.
In addition, neural crest cells migrate throughout the developing embryo and differentiate into melanocytes associated with the epidermis of the skin and supportive neuroglial cells, such as satellite and Schwann cells of the peripheral nervous system.
Abnormalities in the proliferation, migration, and survival of neural crest cells gives rise to numerous syndromes and disorders including aorticopulmonary septal defects and craniofacial abnormalities
DiGeorge syndrome is a primary immunodeficiency disease that results from abnormal neural crest cell migration to the head, neck, and cardiac region. Clinical manifestations include increased susceptibility to infection due to congenital absence of the thymus, disruption in the formation of the parathyroid gland, as well as cardiac abnormalities associated with aorticopulmonary septal defects.
Treacher Collins syndrome results from a failure of neural crest cell to migrate to the region of the developing face, leading to craniofacial abnormalities involving the growth and development of the bones of the face. Patients exhibit hypoplasia of the maxilla and mandible, as well as abnormalities in the external ear.
Hirschsprung disease results from abnormal migration of neural crests cell to the wall of the colon and the failure of the enteric and autonomic ganglion cells to differentiate. Patients exhibit intestinal blockage resulting from impaired peristalsis.
Cranial Sensory Placodes
During the fourth week of embryonic development, a series of bilateral ectodermal thickenings, known as neurogenic placodes, develop in a craniocaudal sequence from the region surrounding the anterior neural plate and cranial neural crest cells. The cranial placodes fall into two broad categories: neurogenic and non-neurogenic placodes.
Neurogenic placodes give rise to neurons associated with the special sensory systems involved in smell and sight.
Olfactory (Nasal) placode differentiate into the bipolar neurosensory epithelial cells of the olfactory nerve (CN I) and induce the development of the olfactory bulbs.
Otic placodes develop into the neurosensory epithelial cells and non-neural epithelium associated with the cochlea and vestibular end organs of the inner ear and neurons of the vestibulocochlear ganglion (CV VII).
The second group of neurogenic placodes differentiates into neurons associated with the cranial sensory ganglia (CN V, VII, IX, and X) of the developing pharyngeal arches in the head and neck region. These placodes develop from ectoderm and neural crest–derived cells and include:
Trigeminal placodes form neurons of the trigeminal ganglion that provide cutaneous sensory innervation to the face and jaw.
Epibranchial placodes develop in association with CNVII, IX, X and are associated with visceral sensory neurons of the geniculate, petrosal, and nodose (inferior) ganglia, respectively. These neurons innervate taste buds and visceral organs.
Two additional ectodermal placodes develop but give rise to non-neurogenic structures:
Optic (lens) placodes—differentiate to form the lens epithelium of the eye. The optic placode develops in association with the optic cup, a neural outgrowth from the developing brain, which gives rise to the retina.
Adenohypophyseal placode (anterior pituitary glands)—differentiates from a thickening of ectoderm in the oral cavity known as Rathke pouch and forms the anterior pituitary gland. The anterior pituitary gland will fuse with the posterior lobe which differentiates from the diencephalon.
Fig. 2.3 Cranial sensory placode formation. Cranial sensory placodes develop as bilateral ectodermal thickenings and differentiate into two groups, neurogenic or non-neurogenic placodes. Neurogenic placodes give rise to special sensory neurons and neuroepithelium that mediate olfaction, hearing, and balance (purple). An additional group of neurogenic placodes develops from ectoderm and neural crest into the sensory neurons associated with cranial sensory ganglia (V, VII, IX, and X) (red). Non-neurogenic placodes develop from ectoderm and give rise to the optic (lens) and anterior pituitary gland (yellow). (Modified with permission from Greenstein B, Greenstein A. Neuroanatomy and Neurophysiology. © Thieme 2000.)
Neural Tube Morphogenesis
During the fourth and fifth week of embryonic development, rapid cellular proliferation within the walls of the neural tube results in hollow swellings, or brain vesicles forming in the rostral end of the neural tube. As the developing brain vesicles rapidly enlarge, folds or flexures form in the rostral neural tube which will enable the developing skull to accommodate the expanding brain. The developing spinal cord develops from the distal portion of the neural tube.
Primary Vesicle and Flexure Development of the Brain ( ).
During the fourth week of development, cranial expansion of the wall of the neural tube leads to the development of three distinct primary brain vesicles:
At the primary vesicle stage, two curvatures, the cephalic and cervical flexures, develop in the rostral neural tube ().
The cephalic (mesencephalic) flexure develops initially as a ventral fold at the level of the midbrain.
The second curvature, known as the cervical flexure, develops on the ventral surface at the junction of the hindbrain and spinal cord.
Secondary vesicle and ventricle development of the brain.
During the end of the fifth week, the three primary vesicle walls continue to expand and become subdivided into five secondary brain vesicles. Concomitantly, the lumen of the rostral neural tube dilates to form a series of four interconnected ventricles (cavities) containing cerebrospinal fluid.
The choroid plexus, which is a vascular network consisting of ependymal cells, develops from the roof of each ventricle and functions in the production of cerebrospinal fluid. The ventricular system communicates with the central canal of the spinal cord, facilitating the circulation of cerebrospinal fluid.
The five secondary brain vesicles include ():
The prosencephalon vesicle divides into the telencephalon and diencephalon.
The walls of telencephalon continue to expand to form two lateral outgrowths, which become the primitive cerebral hemispheres. A ventral outgrowth gives rise to the olfactory bulb.
In the region of the telencephalon, the ventricle dilates and splits to form the two lateral ventricles.
The diencephalon gives rise to bilateral outgrowths which form the optic vesicles, and a ventral evagination, known as the infundibular stalk and neurohypophysis (posterior pituitary). A midline dilation of the lumen in the region of the diencephalon forms the third ventricle.
The lateral ventricles of the telencephalon connect to the third ventricle of the diencephalon through the interventricular foramina (of Monroe).
The mesencephalon remains unchanged, but a narrow groove, the rhombencephalic isthmus, develops and separates the mesencephalon from the rhombencephalon.
The lumen of the mesencephalon narrows to form the cerebral aqueduct that connects the third and fourth ventricles.
The rhombencephalon divides into secondary vesicles known as the metencephalon and myelencephalon.
The pons and cerebellum differentiate from the metencephalon, and the medulla oblongata develops from the myelencephalon.
As the secondary vesicles of the rhombencephalon differentiate, a third flexure, the pontine flexure, develops between the mesencephalic and cervical flexures and demarcates the boundary between the metencephalon and myelencephalon.
The folding of the rhombencephalon at the pontine flexures leads to the formation of the fourth ventricle.
Fig. 2.4 (a,b) Primary brain vesicle formation (dorsal view, neural tube cut open). Three primary vesicles develop from the rostral end of the neural tube due to rapid cellular proliferation. The primary vesicles will give rise to the neural tissue of the forebrain, midbrain, and hindbrain. The spinal cord develops from caudal portion of the neural tube. (Reproduced with permission from Schuenke M, Schulte E, Schumacher U. THIEME Atlas of Anatomy Second Edition, Vol 3. ©Thieme 2016. Illustrations by Markus Voll and Karl Wesker.)
Fig. 2.5 Development of cephalic and cervical flexures. As the brain vesicles expand, the embryo folds forming two flexures: a cephalic (mesencephalic) flexure develops in the midbrain and the second flexure develops at the junction of the hindbrain and spinal cord, as the cervical flexure. (Reproduced with permission from Gilroy AM, MacPherson BR. Atlas of Anatomy. Third Edition. © Thieme 2016. Illustrations by Markus Voll and Karl Wesker.)
Fig. 2.6 Development of secondary brain vesicles and ventricular systems. The three primary vesicles expand and subdivide to form secondary vesicles. The forebrain differentiates into the telencephalon and diencephalon associated with the future cerebral cortex. The hindbrain differentiates into two structures: the metencephalon and myelencephalon. The metencephalon forms the pons and cerebellum. The myelencephalon differentiates into the medulla. As the vesicles differentiate, the lumen of rostral neural tube dilates to form four interconnected cavities known as ventricles that become filled with cerebrospinal fluid (CSF). (Reproduced with permission from Schuenke M, Schulte E, Schumacher U. THIEME Atlas of Anatomy Second Edition, Vol 3. ©Thieme 2016. Illustrations by Markus Voll and Karl Wesker.)
Congenital hydrocephalus is a condition in which cerebrospinal fluid accumulates leading to dilation of the ventricular system. The most common cause of fluid accumulation is obstruction of CSF circulation that results from a narrowing (stenosis) of the cerebral aqueduct. This obstruction, called aqueductal stenosis, may occur during the formation of cerebral aqueduct within the mesencephalon.
Neural Tube Cellular Differentiation
Neuroectoderm lining the lumen of the neural tube differentiates into three layers: an internal layer called the ventricular zone, an intermediate layer called the mantle zone, and an external layer called the marginal zone.
The neuroepithelial stem cells of the ventricular layer undergo rapid cell proliferation and give rise to neuroblasts (neurons), supportive neuroglial cells, and the ependymal cells of the choroid plexus.
Following cellular proliferation in the ventricular layer, neurons migrate to their final destinations within the brain and spinal cord and eventually become organized in a laminar arrangement as the gray matter.
Axons that differentiate from these neurons become organized into groups of ascending and descending tracts and form the white matter of the brain and spinal cord. Nerve fibers that cross the midline from one side of the brain or spinal cord to the other are referred to as commissures, and function to connect the two regions.
