Development of the Nervous System PDF

Phase II Lecture ID# 2308 Development of Central Nervous System Prof. Narayana Kilarkaje FRSB Department of Anatomy Mohammad Alshammari Figures used in this presentation are outsourced from Langman’s Medical Embryology, Netter’s atlas of embryology, and Larsen’s human embryology Objectives Anteri...

Phase II Lecture ID# 2308 Development of Central Nervous System Prof. Narayana Kilarkaje FRSB Department of Anatomy Mohammad Alshammari Figures used in this presentation are outsourced from Langman’s Medical Embryology, Netter’s atlas of embryology, and Larsen’s human embryology Objectives Anterior a posterior • Describe the formation of basal and alar plates in the neural tube,inand development of spinal cord • List the derivatives of cranial part of the neural tube • Describe embryological and molecular basis of congenital anomalies of central nervous system All nervous is system is made of ectoderm. 2 types of ectoderm 1-neuroectoderm( gives to entire nervous system) 2- surface ectoderm ( forms skin epidermis) carity Neural tube formation from neuroectoderm SEE Embryogenesis of CNS begins at 3rd week Neurulation: neural tube formation Neuroectoderm Neural plate Nay Neural groove formation Stimulate Notochord and prechordal mesoderm Elevate and approach each other and fuse making neural tube 1.neuroectoderm is stimulated by notochord (which is below the neuroectoderm) and prechordal mesoderm to Convert ectoderm to neuroectoderm(part of ectoderm is transformed into neuroectoderm) Neural tube Neural crest Ectodermal placode I Notochord is dorsal to neuroectoderm Nerual crest Neruocele in neural tube (cavity) Superior view 16-18d La 20d Some neuroectodermn detach forming neural crest that gives to DRG, sensory. Ganglion, Pia and arachnoid matter, odontoblast Neural crest M a Neural Tube Formation from Ectoderm Neural fold fusion begins on 20d at the cervical region and then extends cranially and caudally Brain Cranial and caudal neuropores fuse on 25d and 28d, respectively The lack of neural fold formation and fusion causes rachischisis- a severe form of neural tube So no fusion, so defect Before closure, they communicate with the amniotic cavity no neural tube 22d 23d Spinal cord dbrain E MPI Cerebellum pts Fate of Neural Tube Medulla Diencephalon elencephalon Tubular caudal part (Spinal cord) Central canal neurocele of SC Enlarged cranial part Primary brain vesicles Prosencephalon (Forebrain) (5 weeks) Telencephalon (Cerebral hemispheres) (Lateral ventricles) Laneurocele of cerebrum andsame for other ventricles Mesencephalon Rhombencephalon (Midbrain) (Hindbrain) (Cerebral aqueduct) 4th ventricle Diencephalon (3rd ventricle) Metencephalon Thalamus Hypothalamus Optic cup and stalk Pons Anterior Cerebellum posterior Myelencephalon (Medulla oblongata) Histology: 3 Layes from inside to outside : 1- Neuroepithelial layer 2- Mantle layer 3- Marginal layer Initially, when neural tube closes there will be only the neuroepithelial layer( also called ependymal layer or matrix layer) these neuroepithelial cells lines the lumen or neruocele, and these neuroepithelial cells has the ability to proliferate and migrates to other layers. And when migrates neuroepithelial cell migrates to mantle layer forms neuron cell< in Mantle layer> (so mantle forms gray matter) and their axons extend into marginal layer( so marginal layer forms white matte ) and the remaining cells in neuroepithelial layer forms ependymal cells that line the lumen of ventricles and canals periderm Gives to dorsal horn of SC 4 pig Gives to ventral horn of SC to if Mj I white Eaten Yes Each lateral wall of the neural tube is divided into basal ( anterior) and alar plate (posterior) by sulcus limitans The basal plate is for motor nuclei, like facial nucleus The alar part is for sensory nuclei, like trigeminal nucleus or 4 Histogenesis of Neural Tube Fig A 24d Surface ectoderm Posterior Neural crest Roof plate Alar plate Basal plate Fig B 5 weeks Migrating neuroblasts Pia mater cells j Neuroepithelial layer Floor plate Anterior motor Ependymal Layer/neuroe pithelial layer Mantle layer neurons Glia blasts Glial cells -Astrocytes -Oligodendrocytes Marginal layer Pia mater Fig C 3 months Mantle zone (Gray mater) Marginal zone (white mater) The neurocele forms the cavity of the brain or spinal cord Neuroepithelial cells are pluripotent Hedidn'tmention it frommesoderm Neuroblasts Ependymal cells Neurocele Ependymal Zone/neuroepithelial Layer/matrix zone t i From neural crest Sulcus limitans ti t by axons Development of the Spinal Cord Mantle layer has sensory neurons i DRG ( contains sensory pseudo-unipolar) developed from neural crest and gives central processes and form dorsal root of spinal nerve that synapse with dorsal horn in SC ( sensory), and from dorsal horn gives tract that ascend up( Basically Ascending tract) Mantle layer has motor neurons • Sulcus limitans divides the developing spinal cord into basal plate and alar plates • The basal plate forms the ventral horn and ventral motor neurons- supply skeletal muscles and preganglionic sympathetic fibers (sonic hedge hog (SHH) gene controls) • The alar plate forms the dorsal horn and its neurons - receive sensations from superficial and deep receptors, and from viscera (bone morphogenetic proteins (BMPs) control) • The roof and floor plates which have no neurons; form pathways for fibers crossing to the other side • Lateral (intermediate) horn develops from the basal plate • Neural crest cells migrate around the developing spinal cord and form neurons and satellite cells of the spinal ganglion • Axons of alar plate neurons penetrate the marginal layer and either ascend or descend as sensory fibers of tracts • Axons of basal plate neurons form the ventral motor root and establish connections with developing muscle Neural Tube Defects (NTDs) Affecting the Spinal Cord Meninges comes out I S1-S2 Not serious If vertebrae not formed properly, there will be an opening, that maybe serious or not No spinous process here, but there is skin, muscle, and normal spinal cord Meninges and SC come out Serious • Abnormal closure of neural folds in 3rd and 4th week, may involve skin, muscles, vertebrae, meninges and spinal cord • Induced by teratogens such as hyperthermia, valproic acid, vitamin A, etc • Incidence is high in some countries (1/200 in China) moderate in other countries (1/1500 in the US), but folic acid supplementation to pregnant women reduces the incidence - 50-70% reduction in NTDs • Do not affect intellectual ability • Spina bifida can be diagnosed by ultrasound (3rd month) coupled with measurement of elevated alfafetoprotein levels in maternal blood In women who drink alcohol and pregnant causes fetal alcohol syndrome that • In utero surgery is the remedy contains NTD ( especially in critical period) at this period maybe she doesn’t know that she’s pregnant, so folic acid is given to women at reproductive age just in case Midbrain Mesencephalon Development of Brain ÉIe alum Algar part Sulcus limitans Myelencephalon Lateral ventricle Metencephalon Thalamus, and hypothalamus Diencephalon rating'ata Cephalic flexure F Cephalic at from Telencephalon Brainstem La Gives to cerebral hemispheres and basal nucleus Diencephalon prosencephalon and mensencephalon I Myelencephalon Cervical flexure Optic stalk At medulla and SC Diencephalon Diencephalon, 2 lateral extensions, optic stalk, forming optic nerve and eyeball Mesencephalon Metencephalon Basalpart Pontine flexure At pons Myelencephalon Sagital section shows 3 exures and please note basal part extends only to mesencephalon, and after that in prosencephalon there is only alar part • • • Lamina terminalis Third ventricle Neural tube on day 36 Fourth ventricle Telencephalon (yellow), 2 vesicles enlarge laterally Cranial part of the neural tube shows prosencephalon, mesencephalon and rhombencephalon making Rt and Lt cerebral hemispheres and cavity Two flexures separate these regions, and the three parts show high cell proliferation extend into each vesicle making 2 lateral ventricles Diencephalon gives rise to bilateral optic stalk and optic vesicles • Basal plates extend only up to mesencephalon, and in the prosencephalon, only alar plate is present, which gives rise to the entire prosencephalon • Prosencephalon forms telencephalon (cerebral cortex, basal nuclei, limbic system, and olfactory system) and diencephalon • The rapid growth of the cranial part of the neural tube results in narrowing of the canal and its realignment as ventricles • Rhombencephalon forms metencephalon (pons and cerebellum) and myelencephalon (medulla oblongata) • Cranial and spinal nerves form and establish connections with structures which they supply Fombatch18 Go Functional organization of the cerebral cortex 1. This is a longitudinal section of the neural tube. You should notice that the basal plate extends only up to the midbrain. However, in the diencephalon & cerebral hemisphere (telencephalon), the basal plate isnt there 2. The whole forebrain (diencephalon & telencephalon) develop from the alar plate only (not from the basal plate as its not there in this area). 1. This is a longitudinal 2 dimensional section: you can see that the forebrain contains 2 lateral vesicles into which the cavity of the neural tube extends in the name of the lateral ventricle. 2. The 2 lateral ventricles open into the 3rd ventricle through a large foramen known as the interventricular foramen. Dr. Abdeslam Mouihate Department of Physiology 3. You can see the sulcus limitans in the picture, it divides the alar plate and basal plate only up to the midbrain, after that, the sulcus limitans is of no significance because ONLY alar plate is there. 3. The third ventricle continues with the cavity of the diencephalon. - The most important thing you should know is the optic stalk (development of the eye). - The development of the eyes starts in the diencephalon. - The olfactory system (for the smell) is developing in the cerebral hemisphere. ** So, olfactory nerve is connected to cerebral hemisphere ** Optic nerve is connected to the diencephalon ** The rest of the cranial nerves are connected to the brain stem. Development of Brainstem from Rhombencephalon Neural tube- 6th week Rhombencephalic junction Roof plate Roof plate of 4th ventricle Rhombic lip IV ventricle Sulcus limitans Rhombencephalon Myelencephalon Metencephalon Mesencephalon Alar plate Pons Medulla The posteior surface of Neural tube at medulla oblongata and pons is not closed Motor nuclei of CN in medulla e.g CN IX + CN Basal plate Floor plate X + CN12 and same thing in Roof of IV ventricle alar for sensory and in pons and midbrain Choroid plexus Pontine nuclei Alar plate Midbrain Colliculus Sensory CN nuclei Motor CN nuclei Inferior olivary nuclei Basal plate Motor CN nuclei Red nucleus • Lateral walls of the rhombencephalon are everted • Basal plate forms the motor nuclei of the cranial nerves, and the alar plate forms the sensory nuclei of cranial nerves • Roof plate remains thin and wide to form the roof of the 4th ventricle • In the developing roof of IV ventricle, choroid plexus covered with pia mater (tela choroidea) is formed • Inferior olivary nuclei and pontine nuclei are formed from migrating cells coming from the alar plate • In midbrain, the alar plate forms the nuclei of colliculi, and red nuclei and substantia nigra (The latter two may also have contribution from the basal plate) • In midbrain, the basal plate forms motor nuclei of cranial nerves III and IV Fombatch18 y Now in the pons, what happens is that not only the alar plate moves away from the midline, but the posterior part of the alar plate now bends medially (this is called the rhombic lip) - this is what produces the cerebellum ** remember: cerebellum develops from the rhombic lip Functional organization of the cerebral cortex 1. As we said, the sulcus limitans divides the neural tube into alar plate and basal plate. The alar plate on each side moves away from the midline to the lateral side, and because of that, the roof plate becomes wider and the cavity becomes bigger (unlike what you saw in the midbrain & spinal cord where the midbrain becomes smaller). That cavity forms the 4th ventricle. Dr. Abdeslam Mouihate Department of Physiology 2. Later on, what happens in the medulla is that, the roof of the developing medulla oblongata becomes broader & thicker and the blood vessels along with the pia mater from the roof of the 4th ventricle envagenate Invaginate into the ventricle forming the choroid plexus. 3. The gray matter in the alar plate forms the sensory nuclei of the cranial nerves. Gray matter in the basal plate forms the motor nuclei of the CN. Alar cells migrate and produce what is called the inferior olivary nucleus in the medulla and pontine nuclei in the pons. (& superior olivary nucleus) ** remember that all of them develop in the alar plate 1. In the midbrain, all of those things dont happen. The cavity of the midbrain becomes smaller and smaller. 2. The dorsal alar plate produces the nuclei of superior and inferior colliculi. Whereas the basal plate produces the cranial nerve nuclei of 3rd and 4th cranial nerves. ** remember: 3rd and 4th cranial nerves nuclei develops from the basal plate of the midbrain 3. The red nucleus and substantia nigra develops from the Alar plate but it is said that they also have contribution from the basal plate 4. fibers that descend down from the cerebral cortex pass in front of the basal plate and produce crus cerebri Development of Cerebellum from Metencephalon Lateral margins of developing pons, there is an extension called cerebellar plate that converges and forms the 2 cereberllar hemispheres 8th to 15th week 8 week 12 week Cerebellar hemisphere Rhombencephalic junction Vermis Flocculus Cerebellar plate Inferior medullary velum Sulcus limitans 8 week Marginal layer 12 week B A External granular layer Matrix layer Purkinje cell layer • Dorsolateral parts of alar plates bend backwards to form rhombic lips which later form cerebellar plates • Flocculonodular lobe gets separated first from the rest of the cerebellum Mantle layer 13 week Nodule 15 week • The cerebellar plates contain outer marginal, middle mantle and inner neuroepithelial (matrix) layers • Neuroepithelial cells migrate to the marginal layer to form the external granular layer, Purkinje cell layer, and basket, Golgi and stellate cells Development of Prosencephalon Telencephalon Mantle layer Ependymal layer A Only alar plate LV Marginal layer Diencephalon B Diencephalon C Hippocampus LV Interventricular foramen III Corpus striatum These 2 vesicles of telencephalon enlarges in anterior, superior, posterior, and inferior direction to make the di erent lobes and makes the cerebral hemisphere to come to the lateral side to cover the diencephalon( so thalamus and hypothalamus inside the cerebral hemispheres Hippocampus D Fornix Corpus callosum Anterior commissure Lamina terminalis Line of division between diencephalon and Medial view of the hemisphere telencephalon • Telencephalic vesicles on either side rapidly increase in size- forwards, upwards and backwards and downwards • This multidirectional growth results in the formation of different lobes of the hemisphere; the cavity extends into these lobes forming different parts of the lateral ventricle • Thus, the telencephalic vesicles cover the lateral surfaces of the diencephalon and fuse with them • Because of apposition of two growing hemispheres, the superior longitudinal fissure is formed, and the mesoderm in it forms the falx cerebri • At the floor of the fissure, the medial wall is thin, and is invaginated by a fold of pia mater and blood vessels forming choroid plexus • Hippocampus follows the C-shaped contour of lateral ventricle, so is the choroid plexus Development of Prosencephalon At medial wall of cerebral, medial ssure and ax cerebri Fig B longitudinal Corpus striatum 0 • Cerebral cortex Neuroepithelial layer At mantle layer of Mantle layer cerebral hemispheres, Marginal layer the neurons develop and • Thalamus C Hypothalamus forms corpus stratium (part of basal nuclei) Epithalamic sulcus Corpus striatum is formed from the lower part of the telencephalon • The cells in the mantle layer proliferate and migrate to the marginal layer to form the cortex • Successively migrating cells pass through the already formed layer to form the superficial layers of the cortex • Cells in the cortex differentiate into different types Fig A Medial view of cerebral • The remaining cells form the corpus striatum hemisphere • Meanwhile, descending axons from the cerebral cortex pass through the developing corpus striatum (internal capsule), thus dividing it into medial caudate nucleus and lateral lentiform nucleus Pineal gland Thalamus Lamina terminalis Hypothalamic sulcus Hypothalamus Later on, diencephalon becomes inside, so lateral to it, is cerebral hemispheres The superior part forms epithalamus (pineal gland and habenular nuclei), the middle part forms the thalamus, and the inferior part forms the hypothalamus • B Optic chiasma The diencephalon becomes thicker and divided into superior, middle and inferior parts by epithalamic and hypothalamic sulci Fig C Caudate nucleus Lentiform nucleus Internal capsule Line of fusion of cerebral hemisphere with diencephalon Further Development of Telencephalon Medial surface Medial wall of cerebral hemisphere in relation to thalamus forms hippocampus Coronal section through the broken line 10-week-old embryo Growth of Brain 3rd month Cerebral hemisphere At 6th month, lobes become clear and even insula( but has th less speed of growth than other lobes) and that’s why it’s deep 6 month 9th month Mesencephalon Cerebellum Diencephalon Pons Insula Insula Spinal cord 90% 100% 75% 50% Postnatal growth of brain 25% Months Birth 6 30 60 120 • Between 7th week and 3rd month of pregnancy, cerebral hemispheres overgrow and cover diencephalon • At 6th month, the developing cerebellum overlies the brainstem dorsally • The cerebral hemispheres grow rostrally, caudally, downward and forward • The cortex lateral to the developing corpus striatum grows at a lesser speed than the surrounding cortex, which results in the formation of insula overlapped by parts of frontal, parietal and temporal lobes • From 6th to 9th month of pregnancy, cerebral cortex forms characteristic gyri and sulci • In cerebellum, the cortex forms folia and fissures Cranial Defects Affecting Brain Development Holoprosencephaly (HPE) • A spectrum of disorders O Only one cerebral hemisphere + one lateral ventricle • Severity varies from simple form in which the patient may have only one incisor tooth to complete fusion of lateral ventricles • Defective midline structures in brain and face • Corpus callosum, olfactory tracts and bulbs are underdeveloped or may be absent • Fused eye, single nasal cavity • 1/15000 cases in live births; 1/250 miscarriage pregnancies • Mutation in Sonic hedgehog (SHH) gene (needed for establishment of the ventral midline) - defective ventralization or cholesterol deficiency (Smith-Lemli-Opitz syndrome; SLO) • SLO children have craniofacial and limb defects, and some have HPE • SLO is autosomal recessive disorder, which causes 7dehydrocholesterol reductase deficiency Schizencephaly • Large cleft between two cerebral hemispheres- due to mutations in homeobox genes (EMX2) Ossification Defects Affecting Brain Development • Ossification defects in skull bones- squamous occipital bone • If the opening is small, only meninges herniate (B) • If the opening in the bone is a bit larger, brain tissue and meninges herniate (C) • Through larger openings, meninges, brain tissue and ventricles herniate (D) • The incidence of meningoencephalocele and meningohydroencephalocele is 1/12000 births Like spina bi da, but not in vertebrate bone ,but in cranium and Usually in occipital bone Occipital meningoencephalocele Neural Tube Defects Affecting the Brain- Anterior Neuropore If anterior neuropore didn’t Closure Defects close or skull cap didn’t develop, the brain is exposed to amniotic uid Excencephaly: • Failure of cephalic part of the neural tube to close, which exposes the brain to amniotic fluid as the cranial vault also does not develop Anencephaly (A): • It is excencephaly in which cranial part of the neural tube or anterior neuropore is not closed • Brain tissue is exposed to amniotic fluid and undergoes necrosis • Brainstem remains intact • Sometimes the closure defect extends into the spinal cord resulting in craniorachischis (B) Spinal cord is exposed • Because these fetuses have swallowing defect, polyhydramnios develops in last two months of pregnancy • Anencephaly occurs in 1/5000 births, common in female fetuses • These neural tube defects can be prevented by pregnant women taking 400 microgram folic acid/day Hydrocephalus and Microcephaly Hydrocephalus: • Accumulation of CSF in ventricles • Due to defects in development of obstruction of normal route of CSF flow, usually at cerebral aqueduct At midbrain • Because cranial bones are not yet fused in fetuses, the enlarging brain not only thins the bones but also separates them I Microcephaly: • Cranial vault is smaller because underlying brain is smaller • May be caused by teratogens, hyperthermia (sauna bath), intrauterine insults, or genetic factors (autosomal recessive) • Intellectual disability is evident Reference Langman’s Embryology, 13th Edition, Chapter 18: Central nervous system & Chapter 20: Eye