Embryological development of the nervous system and special

postgraduate surgery presentation

1. EMBRYOLOGICAL DEVELOPMENT OF THE NERVOUS SYSTEM AND SPECIAL SENSES PRESENTER: DR PASHI V M MODERATOR: PROF MUNKONGE

2. Neurulation The notochord induces overlaying ectoderm to become neuroectoderm and form a neural tube . The following stages of neural tube formation are evident: neural plate —ectodermal cells overlaying the notochord become tall columnar, producing a thickened neural plate (in contrast to surrounding ectoderm that produces epidermis of skin ).

3. neural groove —the neural plate is transformed into a neural groove. neural tube —the dorsal margins of the neural groove merge medially, forming a neural tube composed of columnar neuroepithelial cells surrounding a neural cavity . In the process of separating from overlaying ectoderm, some neural plate cells become detached from the tube and collect bilateral to it, forming neural crest .

4. The three germ layers are formed at gastrulation Ectoderm : outside, surrounds other layers later in development, generates skin and nervous tissue. Mesoderm : middle layer, generates most of the muscle, blood and connective tissues of the body and placenta. Endoderm : eventually most interior of embryo, generates the epithelial lining and associated glands of the gut , lung , and urogenital tracts.

5. Neural Induction: In addition to patterning the forming mesoderm, the primitive node also sets up the neural plate Ectoderm exposed to BMP-4 (from endoderm and mesoderm below), develops into skin However, the node secretes BMP-4 antagonists: (e.g. noggin, chordin, & follistatin ) that allow a region of the ectoderm to develop into nerve tissue.

6. Neurulation: folding of the neural plate Median hinge point forms (probably due to signaling from notochord) –columnar cells adopt triangular morphology (apical actin constriction, like a purse string) Lateral hinge point forms by a similar mechanism (probably due to signaling from nearby mesoderm). As neural folds close, neural crest delaminates and migrates away (more on that later…) Closure happens first in middle of the tube and then zips rostrally and caudally .

7. Neurulation: folding and closure of the neural plate Folding and closure of the neural tube occurs first in the cervical region. The neural tube then “zips” up toward the head and toward the tail, leaving two openings which are the anterior and posterior neuropores . The anterior neuropore closes around day 25. The posterior neuropore closes around day 28.

8. Failure of neuropores to close can cause neural tube defects anterior neuropore : anencephaly posterior neuropore : spina bifida

9. Failure of the anterior neuropore to close results in anencephaly In this defect, the brain is not formed , the surrounding meninges and skull may be absent, and there are facial abnormalities. The defect extends from the level of the lamina terminalis , the site of anterior neuropore closure, to the region of the foramen magnum . An encephalocele is a herniation of intracranial contents through a defect in the cranium ( cranium bifidum ).

10. The cystic structure may contain only meninges ( meningocele ), meninges plus brain ( meningoencephalocele ), or meninges plus brain and a part of the ventricular system ( meningohydroencephalocele ). Encephaloceles are most common in the occipital region, but they may also occur in frontal and parietal locations

11. SPINAL CORD Neuro tissue development The neuro tube is made up of neuro epithelial cells that divide and form the neuroepithelium Some cell divisions are differential, producing neuroblasts which give rise to neurons or glioblasts (spongioblasts) which give rise to glial cells Neuroblasts and glioblasts lose contact with surfaces of the neural tube and migrate toward the centre of the neural tubewall.

12. Accumulated neuroblasts and glioblasts form the mantle layer , a zone of high cell density in the wall of the neural tube. Cells that remain lining the neural cavity are designated ependymal cells; they form an ependymal layer. Surrounding the mantle layer, a cell sparse zone where axons of neurons and some glial cells are present is designated the marginal layer. The mantle layer becomes gray matter Marginal layer becomes white matter of the CNS.

13. The developing neural tube is divided into 4 plates Roof plate: signaling center (BMPs and Wnts ) Alar plate: sensory Basal plate: motor Floor plate: signaling center ( Shh )

14. The lateral wall of the neural tube is divided into two regions (plates). A bilateral indentation evident in the neural cavity (the sulcus limitans ) serves as a landmark to divide each lateral wall into an alar plate (dorsal) and a basal plate (ventral). Midline regions dorsal and ventral to the neural cavity constitute, respectively , the roof plate and the floor plate.

15. Spinal cord development The neural cavity becomes central canal lined by ependymal cells; G rowth of alar and basal plates, but not roof and floor plates, results in symmetrical right and left halves separated by a ventral median fissure and a dorsal median fissure (or septum); The mantle layer develops into gray matter, T he marginal layer becomes white matter

16. Regression” of the spinal cord The spinal cord and the vertebral column are the same length up until the 3 rd month. As each vertebral body grows thicker, the overall length of the vertebral column begins to exceed that of the spinal cord such that , in the adult the spinal cord terminates at L2 or 3 and the dural sac ends at about S2. The tail end of the dural sac covering the spinal cord and nerve roots remains attached at the coccyx and becomes a long, thin strand called the filum terminale. Sometimes, the spinal cord can become “tethered” or attached to the dural sac or filum terminale; this pulls on the cord and can obstruct flow of CSF thus causing swelling of the ventricles of the brain (hydrocephalus),

17. CNS CELLS

18. NEURAL CREST CELLS the “4th germ layer” At the time of neurulation , cells at the lateralmost edge of the neural plate are exposed to a unique combination of factors from the adjacent skin, underlying mesoderm, and from the rest of the neural plate and are induced to form neural crest. The neural crest cells downregulate cadherin expression and delmainte from the neuroepithelium, i.e., they transform from epithelial cells into migratory mesenchymal cells that contribute to forming MANY tissues in the body.

19. Major Derivatives of the Neural Crest

20. Trunk Neural Crest: sensory lineage Migrate along ventrolateral stream and stop just medial to somite Aggregate into dorsal root ganglia and separate into 2 general lineages: Sensory neurons (Wnts, NGFs, bHLHs (Ngn1, etc.) Glia (Schwann cells and satellite cells) via GDNF signaling Sensory neurons extend processes in two directions: dorsomedially to neural tube and ventrolaterally into growing spinal nerve (established by outgrowth of motor neuron axons from the ventral horn)

21. Innervation is segmental (dermatomes)

22. Sensory neurons send axons into dorsal horn. Motor neurons send axons out of vental horn. Axons of peripheral nerves are myelinated by Schwann cells

23. Trunk Neural Crest: sympathoadrenal lineage Migrate along ventral stream Dependent on expression of Phox-2 and Mash-1 BMPs from aorta play further instructive role to specify bi-potential progenitors: Sympathetic ganglion neurons: induced by presence of FGF and NGF in symp. Ganglia Adrenal chromaffin cells: induced by glucocorticoids in adrenal gland

24. Circumpharyngeal Neural Crest: vagal crest Migrate caudal to 6 th arch and then become associated with wall of fore-, mid-, and proximal hindgut Downregulate expression of Robo, a Slit-2 receptor, which allows them to invade the gut wall. Hand2 influences differentiation into cholinergic phenotype

25. Innervation of the Gut: vagal and lumbosacral crest Vagal crest: innervate gut wall from foregut to ~proximal 2/3 of transverse colon in hindgut Sacral crest: innervate hindgut wall from ~distal 1/3 of transverse colon to rectum

26. Circumpharyngeal Neural Crest: Associated with arches 3,4,6 Contribute to thyroid, parathyroid, and thymus Cardiac crest contributes to outflow tract cushions Disturbances (e.g. DiGeorge syndrome, Hoxa-3 mutation) therefore have multiple effects: craniofacial (jaw) defects, glandular defects, & outflow tract defects

27. Cranial Neural Crest: Contribute to forehead, face, jaw, and pharyngeal arch derivatives

28. THE BRAIN Divided into brain stem and higher centres Distinct basal and Alar plates found on each side of the midline in the rhombencephalon and mesencephalon . In the prosencephalon the alar plates are accentuated and the basal plates regress

29. Primary Brain Vesicles The cranial end of the neural tube forms three vesicles (enlargements ) that further divide into the five primary divisions of the brain . Caudal to the brain the neural tube develops into spinal cord . Flexures: During development, the brain undergoes three flexures which generally disappear

30. The midbrain flexure occurs at the level of the midbrain. The cervical flexure appears at the junction between the brain and spinal cord The pontine flexure is concave dorsally (the other flexures are concave ventrally).

31. Primary brain vesicles

32. Secondary Brain Vesicles During the fifth week, the three primary brain vesicles are divided into five secondary brain vesicles. This requires two additional flexures. The pontine flexure divides the hindbrain into the myelencephalon caudally and the metencephalon rostrally . The mesencephalon does not partition further .

33. The telencephalic flexure (shortened here from the longer term diencephalic- telencephalic sulcus ) divides the forebrain into the diencephalon caudally and the telencephalon rostrally . The telencephalon (meaning “end-brain”) forms as an outpocketing of the forebrain and expands enormously, with its complex lobes, gyri, and sulci, to become the largest part of the brain

34. Major divisions of the developing brain: 3 parts, then 5 parts 3 parts: Prosen -, Mesen -, and Rhomencephalon 5 parts: Prosencephalon divides into telen - and diencephalon, Rhombencephalon divides into met- and myelencephalon

35. Major divisions of the developing brain: 3 parts, then 5 parts

36. Hindbrain: Medulla oblongata and pons alar plates move laterally and the cavity of the neural tube expands dorsally forming a fourth ventricle; the roof of the fourth ventricle (roof plate) is stretched and reduced to a layer of ependymal cells covered by pia mater; a choroid plexus develops bilaterally in the roof of the ventricle and secretes cerebrospinal fluid ;

37. the basal plate (containing efferent neurons of cranial nerves) is positioned medial to the alar plate and ventral to the fourth ventricle; white and grey matter (marginal & mantle layers) become intermixed (unlike spinal cord); Cerebellar development adds extra structures.

38. Hind brain

39. Development of the myelencephalon Alar plate develops into 4 sensory tracts: Olivary nucleus (cerebellar input) Somatic afferent (general sensation from the face, via CN V, external ear, auditory meatus, and eardrum via CN IX, X) Special visceral afferent (taste, CN IX, X) General visceral afferent (autonomic input, CN IX, X) Basal plate develops into 3 motor tracts: General visceral efferent (autonomic output, CN IX, X) Special visceral efferent (innervation of pharyngeal arch muscles of the larynx & pharynx, CN IX, X, XI) Somatic efferent (innervation of skeletal muscles of the tongue, CN XII) (covered by ependymal cells that produce CSF)

40. Midbrain the neural cavity of the midbrain becomes mesencephalic aqueduct (which is not a ventricle because it is completely surrounded by brain tissue and thus it lacks a choroid plexus).

41. alar plates form two pairs of dorsal bulges which become rostral and caudal colliculi (associated with visual and auditory reflexes, respectively); the basal plate gives rise to oculomotor (III) and trochlear (IV) nerves which innervate muscles that move the eyes. Note: The midbrain is the rostral extent of the basal plate (efferent neurons).

42. Development of the mesencephalon Alar plate generates superior and inferior colliculi Inferior colliculus: auditory relay Superior colliculus: visual relay Basal plate generates 4 motor tracts: Somatic efferent (motor output to extraocular muscles, CN III, IV) Visceral efferent (motor output to ciliary ganglion of the eye, CN III) Red nucleus (motor relay to flexor muscles of the upper limb) Substantia nigra (dopaminergic output to the basal ganglia of the telencephalon)

43. Forebrain derived entirely from alar plate Diencephalon: the neural cavity expands dorsoventrally and becomes the narrow third ventricle , the roof plate is stretched and choroid plexuses develop bilaterally in the roof of the third ventricle and secrete cerebrospinal fluid; the floor of the third ventricle gives rise to the neurohypophysis (neural lobe of the pituitary gland );

44. the mantle layer of the diencephalon gives rise to thalamus, hypothalamus, etc.; the thalamus enlarges to the point where right and left sides meet at the midline and obliterate the center of the third ventricle. the optic nerve develops from an outgrowth of the wall of the diencephalon.

45. Telencephalon (cerebrum): bilateral hollow outgrowths become right and left cerebral hemispheres ; the cavity of each outgrowth forms a lateral ventricle that communicates with the third ventricle via an interventricular foramen (in the wall of each lateral ventricle, a choroid plexus develops that is continuous with a choroid plexus of the third ventricle via an interventricular foramen );

46. at the midline, the rostral end of the telencephalon forms the rostral wall of the third ventricle (the wall is designated lamina terminalis ); the mantle layer surrounding the lateral ventricle in each hemisphere gives rise to basal nuclei and cerebral cortex ;

47. Development of the diencephalon Pineal gland: sleep-wake cycle, secretes melatonin Epithalamus: masticatory and swallowing functions Thalamus: major relay of sensory input to cerebral cortex Hypothalamus: master regulatory center (autonomic and endocrine) and also limbic system (emotion & behavior) Hypophysis/infundibulum: posterior pituitary gland, secretes ADH and oxytocin Optic cup: retina of eye

48. Ventricular System The ventricular system is an elaboration of the lumen of cephalic portions of the neural tube, and its development parallels that of the brain. The cavities of the telencephalic vesicles become the lateral ventricles ; T he diencephalic cavity becomes the third ventricle ; T he rhombencephalic cavity becomes the fourth ventricle .

49. The cavity of the mesencephalon becomes the narrow cerebral aqueduct ( of Sylvius ) connecting the third and fourth ventricles, The openings between the lateral ventricles and the third ventricle become the intraventricular foramina ( of Monro ). The ventricular system is lined with ependymal cells . Each ventricle originally has a thin roof composed of an internal layer of ependyma and an outer layer of delicate connective tissue ( pia mater ). In each ventricle, blood vessels invaginate this membrane to form the choroid plexus .

50. Openings that arise in the caudal roof of the fourth ventricle during development form a communication between the ventricular system and the subarachnoid space. These are the midline medial aperture ( foramen of Magendie ) and the paired lateral foramina of Luschka . Although these foramina develop slowly , they are patent by the end of the first trimester. CSF is produced mainly by the choroid plexuses of the lateral and third ventricles .

51. It escapes the ventricular system through foramina of the fourth ventricle and passes into the subarachnoid space. From there, it is absorbed into the venous system through the arachnoid villi located primarily in the superior sagittal sinus. If the flow of CSF through the ventricles is obstructed during prenatal development, the ventricular system can become markedly dilated, a condition called congenital hydrocephalus

52. HYDROCEPHALUS

53. Formation of Meninges Meninges surround the CNS and the roots of spinal and cranial nerves. Three meningeal layers (dura mater, arachnoid, and pia mater) are formed as follows: mesenchyme surrounding the neural tube aggregates into two layers; the outer layer forms dura mater; cavities develop and coalesce within the inner layer, dividing it into arachnoid and piamater ; the cavity becomes the subarachnoid space which contains cerebrospinal fluid.

54. PERIPHERAL NERVOUS SYSTEM The peripheral nervous system develops mostly from cells of the neural crest. Placodes Specialized epidermal cells called placodes are found in the developing head region. These will join neural crest cells, together placodes and neural crest form the ganglia of cranial nerves V, VII, VIII, IX, and X .

55. Cranial Nerve Ganglia Cranial nerves V (trigeminal nerve), VII (facial nerve), IX ( glossopharyngeal nerve ), and X ( vagus nerve) have sensory ganglia that originate from neural crest and placode cells They contain pseudounipolar cell bodies. These are the trigeminal or semilunar (V ) ganglion, the geniculate ganglion (VII), the superior and inferior (IX) ganglia of the glossopharyngeal nerve, and the jugular and nodose (X) ganglia of the vagus nerve.

56. Spinal nerves Posterior (Dorsal) Root Ganglia Pseudounipolar cells of posterior , or dorsal , root ganglia are derived from the neural crest . Each spinal nerve and its corresponding ganglion are associated with a segment (or somite ) of the developing embryo.

57. The segmental nature of the embryo is reflected in the segmental sensory innervation of the body These segments, known as dermatomes , are important in the diagnosis of many neurologic disorders.

58. Innervation is segmental (dermatomes)

59. Visceral Motor System The postganglionic sympathetic and parasympathetic neurons of the visceral motor system are also derived from the neural crests . Some of these cells remain near their site of origin to form the sympathetic chain ganglia adjacent to the vertebral column. Other cells migrate with branches of the aorta to form the sympathetic prevertebral ganglia .

60. Most of the autonomic ( visceromotor ) neurons of the digestive tract ( Auerbach and Meissner plexuses) are formed by neural crest cells that migrate from the area of the rhombencephalon . Consequently, these cells receive vagal innervation in the adult. Visceromotor (autonomic) neurons of the descending colon and pelvic structures are derived from neural crest cells that arise from sacral cord levels during secondary neurulation

61. The human syndrome congenital megacolon ( Hirschsprung disease ). neurons forming the enteric ganglia fail to migrate into the lower bowel. In the absence of these cells, no sensory signal indicating the presence of feces in the colon is sent to the CNS. Therefore, no motor signal is sent to control defecation.

62. Trunk Neural Crest: sympathetic nervous system

63. Parasympathetic Nervous System: derived from cranial, vagal, and lumbosacral crest

64. Special senses Formation of the Eye The developing eye appears in the 22-day embryo as a pair of shallow grooves on the sides of the forebrain Both eyes are derived from a single field of the neural plate. The single field separates into bilateral fields associated with the diencephalon.

65. The following events produce each eye: a lateral diverticulum from the diencephalon forms an optic vesicle attached to the diencephalon by an optic stalk ; a lens placode develops in the surface ectoderm where it is contacted by the optic vesicle; the lens placode induces the optic vesicle to invaginate and form an optic cup while the placode invaginates to form a lens vesicle that invades the concavity of the optic cup ;

66. an optic fissure is formed by invagination of the ventral surface of the optic cup and optic stalk, and a hyaloid artery invades the fissure to reach the lens vesicle; The optic cup forms the retina and contributes to formation of the ciliary body and iris . The outer wall of the cup forms the outer pigmented layer of the retina, and the inner wall forms neural layers of the retina. The optic stalk becomes the optic nerve as it fills with axons traveling from the retina to the brain .

67. The lens vesicle develops into the lens , consisting of layers of lens fibers enclosed within an elastic capsule. The vitreous compartment develops from the concavity of the optic cup , and the vitreous body is formed from ectomesenchyme that enters the compartment through the optic fissure . ectomesenchyme (from neural crest) surrounding the optic cup condenses to form inner and outer layers, the future choroid and sclera , respectively ;

68. the ciliary body is formed by thickening of choroid ectomesenchyme plus two layers of epithelium derived from the underlying optic cup; the ectomesenchyme forms ciliary muscle and the collagenous zonular fibers that connect the ciliary body to the lens; the iris is formed by choroid ectomesenchyme plus the superficial edge of the optic cup; The outer layer of the cup forms dilator and constrictor muscles and the inner layer forms pigmented epithelium;

69. the ectomesenchyme of the iris forms a pupillary membrane that conveys an anterior blood supply to the developing lens ; when the membrane degenerates following development of the lens, a pupil is formed; the cornea develops from two sources: the layer of ectomesenchyme that forms sclera is induced by the lens to become inner epithelium and stroma of the cornea, while surface ectoderm forms the outer epithelium of the cornea;

70. the anterior chamber of the eye develops as a cleft in the ectomesenchyme situated between the cornea and the lens; the eyelids are formed by upper and lower folds of ectoderm, each fold includes a mesenchyme core; the folds adhere to one another but they ultimately separate prenatally. ectoderm lining the inner surfaces of the folds becomes conjunctiva , and lacrimal glands develop by budding of conjunctival ectoderm ;

71. skeletal muscles that move the eye (extraocular eye mm.) are derived from rostral somitomeres (innervated by cranial nerves III, IV, and VI ).

72. Formation of the Ear The ear has three components: external ear, middle ear, and inner ear. The inner ear contains sense organs for hearing (cochlea) and detecting head acceleration (vestibular apparatus), the latter is important in balance. Innervation is from the cochlear and vestibular divisions of the VIII cranial nerve.

73. The middle ear contains bones ( ossicles ) that convey vibrations from the tympanic membrane (ear drum) to the inner ear. The outer ear channels sound waves to the tympanic membrane.

74. Inner ear: an otic placode develops in surface ectoderm adjacent to the hindbrain; the placode invaginates to form a cup which then closes and separates from the ectoderm, forming an otic vesicle ( otocyst ); an otic capsule , composed of cartilage, surrounds the otocyst ; some cells of the placode and vesicle become neuroblasts and form afferent neurons of the vestibulocochlear nerve (VIII);

75. the otic vesicle undergoes differential growth to form the cochlear duct and semicircular ducts of the membranous labyrinth; some cells of the labyrinth become specialized receptor cells found in maculae and ampullae ; the cartilagenous otic capsule undergoes similar differential growth to form the osseous labyrinth within the future petrous part of the temporal bone.

76. Middle ear: the dorsal part of the first pharyngeal pouch forms the lining of the auditory tube and tympanic cavity the malleus and incus develop as endochondral bones from ectomesenchyme in the first branchial arch and the stapes develops similarly from the second arch

77. Outer ear: the tympanic membrane is formed by apposition of endoderm and ectoderm where the first pharyngeal pouch is apposed to the groove between the first and second branchial arches; the external ear canal (meatus) is formed by the groove between the first and second branchial arches ; the arches expand laterally to form the wall of the canal and the auricle (pinna) of the external ear.

78. Taste buds Taste buds are groups of specialized (chemoreceptive) epithelial cells localized principally on papillae of the tongue. Afferent innervation is necessary to induce taste bud formation and maintain taste buds . Cranial nerves VII (rostral two-thirds of tongue) and IX (caudal third of tongue) innervate the taste buds of the tongue.

79. Olfaction Olfaction (smell) involves olfactory mucosa located caudally in the nasal cavity and the vomeronasal organ located rostrally on the floor of the nasal cavity. Olfactory neurons are chemoreceptive; their axons form olfactory nerves (I). an olfactory (nasal) placode appears bilaterally as an ectodermal thickening at the rostral end of the future upper jaw;

80. the placode invaginates to form a nasal pit that develops into a nasal cavity as the surrounding tissue grows outward; in the caudal part of the cavity, some epithelial cells differentiate into olfactory neurons; the vomeronasal organ develops as an outgrowth of nasal epithelium that forms a blind tube; some epithelial cells of the tube differentiate into chemoreceptive neurons.

81. REFENCES Langmans’s Medical Embryology, 12 th ed Phillip M. Ecker et al, An animated tour of human development, version 1.1.