Development and Plasticity of Cortical Circuits: Part I: Overview of nervous system development Normal and abnormal development of spinal cord and neocortex
2021
Daniel J. Felleman
Department of Neurobiology & Anatomy McGovern Medical School
Office: MSB 7.168 Telephone: 500-5629 Email: [email protected] Basic Nervous System Development Normal and Abnormal Development of Neocortex
• Neurogenesis • Development of notochord and neural plate • Genetic/Molecular Determinants of cell fate/function in spinal cord • Abnormal neural tube development: spina bifida • Overview of development of neocortex • Tangential and radial migration of neural progenitors • Abnormal neocortical development Normal and Abnormal Cortical Development
• Neurogenesis • Determination of Cell Fate • Radial and Tangential Neuroblast migration • Morphology and genetic bases for some known errors in cortical development Dividing precursor cells of the neuroepithelium: Cyclical movement of precursor cells from ventricular surface to pial surface. In mitotic phase, symmetrical division leads to two neural stem cells while asymmetrical division leads to undifferentiated neuroblast and progenitor cell Review of Gastrulation and Nervous System Induction
ECTODERM
MESODERM
ENDODERM Paraxial Mesoderm Forms Somitomeres and Somites Carnegie stage 10: approximately 20 days 4-5 pairs of Somites Somitomeres first appear in the cranial region and are added caudally.
Somitomeres 1-7 do not form somites, but form the musculature of the face, jaw, and throat.
Somitomeres 8-10 differentiate into the first, second, and third pairs of somites at ~day 20. Development of Body Form in Week 4 ~ Day 20 ~ Day 23
~ Day 24 ~ Day 28 By the end of the fifth week, there are 42 to 44 pairs of somites.
Some degenerate in the caudal-most region, for a final somite count of 37 or 38 pairs. Formation of the Notochord I: Key step in formation of neural tube
The notochordal process forms within the mesoderm at the caudal end of the primitive pit, extends cranially and forms a lumen that becomes the notochordal canal. Formation of the Notochord II
• The floor of the notochordal process then fuses with the endoderm • The floor then breaks down forming a transient opening between the amniotic cavity and yolk sac; the neuroenteric canal • The roof of the notochord thickens, forms the notochordal plate Formation of the Notochord III
The notochordal plate then invaginates to form the tubular notochord buried within the mesoderm. Germ Layer Derivatives
Surface ectoderm forms the epidermis of the skin , mammary glands, subcutaneous glands, hair, enamel of teeth, inner ear and lens of eye.
Surface ectoderm is induced to form neuroectoderm by the blockade of BMP4 by chordin, noggin, and follistatin (from notochord)
Neuroectoderm forms the neural crest and neural tube.
Mesoderm: (paraxial, intermediate, and lateral)
Paraxial mesoderm: will give rise to somitomeres; segmental blocks of mesoderm that first arise in the head region and are added ~3-4/day.
The first 7 pairs do not form somites, but form portions of face, jaw and throat. Formation of the Neural Tube I Neural Induction:
• The primitive pit and notochord function as an inducers of the overlying ectoderm to form the neural ectoderm and then neural plate
• Cranially the neural plate extends nearly the full width of the embryo.
• By ~ day 18 or 19 the neural plate invaginates, forms a central neural groove flanked by neural folds
• The neural folds fuse to form neural tube and the neural crest will pinch off and migrate Formation of the Neural Tube II: Fusion
• Primary neurulation: The neural folds fuse to form most of the neural tube by ~day 27-28
• Fusion begins in the cervical region and proceeds cranially and caudally (up to 5 closure sites)
• The anterior neuropore closes by day ~25-26
• The posterior neuropore closes by day ~27- 28
• The neural tube formed by the close of the caudal neuropore only extends through somite 31
• Secondary neurulation forms the sacral regions of the neural tube that later joins with the primary neural tube by ~ day 40 Another look at Neurulation
Five closure sites Defects in Neural Tube Closure *sites 1,5= spina bifida *site 2= anencephaly Neural Tube Defects
• Neural Tube Defects (NTD) are associated with closure defects of the rostral and/or caudal neuropores and defects in vertebral arch development • Severe defects occur ~ 1:1000, but the incidence varies geographically with a high of 1:200 in northern China; perhaps associated with low levels of dietary folate • Overall US rate is now 1:1500 • It is estimated that 50-70% of NTDs can be prevented if women take 400 µg of folic acid daily beginning 3 months prior to conception and throughout pregnancy Neural Tube Closure Defects
• Spina bifida occulta: lack of fusion of vertebral arches occurs in ~10% of normal people; tuft of hair • Spina bifida cystica: neural tissue and/or meninges protrude through defect in vertebral arch Meningocele: only meninges protrude Meningomyelocele: meninges and spinal cord protrude • Raschischisis or myeloschisis : open neural tube; exposed to amniotic fluid and leads to necrosis Spina bifida cystica Spina bifida occulta Meroencephaly
Anencephaly or Myeloschsis cranio-rachischisis Anencephaly • Failure of closure of the rostral aspect of the neural tube with the inciting event occurring no later than the 26th day of gestation • Polyhydramnios is frequently noted • 75% of affected fetuses are stillborn with the remainder dying in the neonatal period • Etiologies believed to be environmental and genetic in nature Encephalocele • Condition where there is protrusion of cerebral tissue through a defect in the cranium. Usually located in the frontal (eastern hemisphere) or occipital regions (western hemisphere) • The tissue that is protruding is usually not viable • Believed to occur at the time of closure of the anterior neuropore (before 26th day of gestation). May be the only major malformation present in an infant Neural Crest Origin and Migration (‘fourth germ layer of embryo’)
Cranial neural crest cells migrate to form tissues and bones in face and neck, pharyngeal arches 1-4/6, and epibranchial placodes V, VII, IX, and X. Neural Crest: Origin and Destinations
Other derivatives include:
• Conotruncal septum of heart Odontoblasts • Spinal (dorsal root) ganglia Sympathetic chain ganglia Parasympathetic ganglia of GI track • Adrenal medulla, • Schwann cells • Forebrain meninges Melanocytes • Smooth muscle cells to blood vessels in head • Facial skeleton • Eye development Abnormalities Due To Neural Crest Defects
• Hirshsprung’s disease • Aorticopulmonary septation defect of the heart • Cleft lip, cleft palate • Fronto-nasal dysplasia • Di George Syndrome- hyperthyroidism, thyroid deficiency, thymic dysplasia • CHARGE association: coloboma of the retina, lens or choroid, heart defects (e.g. tetralogy of Fallot, VSD, PDA), atresia choanae, retardation of growth, genital abnormalities in males, ear abnormalities or deafness • Neurofibromatosis- peripheral nerve tumors • Neuroblastoma- tumor of the adrenal medulla, autonomic ganglia Brain Vesicles
Primary vesicles Secondary vessicles arise during 5th week apparent by day 26 Spinal Cord Development I
Sulcus limitans
Sulcus limitans (up through midbrain) separates alar and basal plates. Alar plate: sensory nuclei Basal plates: motor neurons Spinal Cord Development II
Ventricular zone: (ependymal layer) adjacent to central canal contains neuroepithelial precursor cells which form all neurons and microglia of spinal cord. Neuroblasts migrate from ventricular to intermediate zone. Marginal zone contains long, inter-segmental, and local axons Neural Histogenesis
• Mesenchymal cells differentiate into microglia • Neuroblasts from neuroectoderm differentiate into multiple neuron types; e.g. bipolar, unipolar • Glioblasts will form the astrocytes and oligodendrocytes • After glioblast differentiation, the neuroepithelial layer will differentiate into the ependymal cell lining of the ventricles and central canal of the spinal cord. Myelination
PNS
CNS
•In the peripheral nervous system, Schwann cells (derived from neural crest) wrap themselves around sensory, motor and autonomic motor axons •In the spinal cord (CNS), myelin sheaths are formed from oligodendrocytes •Myelination is a prolonged process; peripheral nerves are myelinated beginning around 20 weeks, while myelination of fiber pathways in the brain continues well after birth •Myelination of the cerebral cortex is very prolonged and progresses largely in a posterior to anterior sequence •Pre-frontal cortex is the last region to be myelinated whereas primary sensory areas are myelinated first Molecular Regulation of Neuroblast Fate in Spinal Cord (and Cortical Plate)
Sonic Hedgehog is initially secreted by the notochord and induced to be secreted by the floor plate of the developing neural tube BMP4 is initially secreted by the surface ectoderm and induced to be secreted by the roof plate These bi-directional gradients restrict the fate of neuroblasts of the neural tube to develop into dorsally situated sensory neurons and ventrally situated motor neurons Generation of cortical neurons during gestation of rhesus
• Neuronal birth-dating with either 3H-thymidine or BrDU (bromo-deoxyuridine) • First born neurons form the transient sub-plate layer • Next born reach cortical layer 1 (marginal zone). • Remaining neurons are born and migrate in an inside-out order; L 6,5,4,3 and 2. Radial Migration/Differentiation of the Cerebral Cortex
MZ Marginal zone CP Cortical plate SP Sub-plate zone IZ Intermediate zone VZ Ventricular zone SZ Sub-ventricular zone WM White matter
Neuroblast proliferation begins in the ventricular zone The marginal zone is formed above the ventricular zone, followed by the intermediate zone and cortical plate. Later neuroblast proliferation shifts to the subventricular zone and a transient layer, the sub-plate is formed. Subplate neurons form transient synapses with ingrowing axons from the thalamus and serve as axonal place-holders until the cortical layers are more fully developed. Radial Migration into Cerebral Cortex
Marginal zone then inside out! Neuroblast Differentiation and Radial Migration
Contrary to traditional views, radial glia are now viewed as important sources of neuroblasts Through initial asymmetric division to form intermediate progenitor cells (nIPG) followed by symmetric cell division to yield additional nIPG and then neuroblasts. Radial glia are also thought to give rise to astrocytes (direct transformation) as well as oligodendrocyte progenitors (oIPC). Tangential Migration of Inhibitory Interneurons
Radial migration of excitatory neurons Tangential migration of inhibitory interneurons Tangential migration II
Migrating neuroblasts from the Medial ganglionic eminence (MGE) became GABA interneurons of the cortex Migrating neuroblasts from the Lateral ganglionic eminence (LGE) become GABA interneurons of the olfactory bulb ,a small subset of interneurons of the cortex, and oligodendroglia of the forebrain. Medial eminence gives rise to Basket cells, Chandelier cells, Martinotti cells, and Neurogliaform cells ((somatostatin- and parvalbumen-containing GABA neuron sub-types)) Caudal eminence gives rise to the Double Bouquet cells (VIP-containing neurons) Lateral eminence gives rise to a small fraction of cortical interneurons, but not PV or SST- containing (also olfactory bulb)
Molnar et al 2019 Lineage of Neural Stem Cells
Embryonic neurogenesis: arise from early radial glia and neuronal intermediate precursors Adult neurogenesis is thought to continue from B cells (astrocyte-like) of the subventricular zone. Adult neurogenesis within the hippocampus is thought to arise from SGZ (sub-granular zone) radial glia yielding nIPCs. Molecular Signals Critical for Radial Migration: Potential contributions to errors in cortical development
Key steps include control of proliferation, adhesion to radial glia, movement along glia, and recognition of cortical plate position. Processes and Molecules Critical for Cortical Development
• Proliferation/apoptosis:(e.g. microcephaly) genes associated with centrosome proteins and DNA repair • Migration: (e.g. lissencephaly, Lis1; heterotopias or double cortex, DCX) cytoskeleton stability and extracellular matrix interactions • Organization: (e.g. polymicrogyria) not well understood, but suggest cell-cell recognition errors DISORDERS OF NEURONAL AND GLIAL PROLIFERATION AND MIGRATION
• Lissencephaly: Lissencephaly means 'smooth brain,' i.e., brain without convolutions or gyri. Also characterized by thickened, disorganized cortex • Deletion of, or mutation, in the LIS1 gene (PAFAH1B1; 601545) appears to cause the lissencephaly because point mutations have been identified in this gene in isolated lissencephaly sequence (ILS; see 607432). • A failure of neuronal migration and cortical organization results; infants often have difficulty with seizures, abnormal neurologic examination, and intellect Disorders of Neuroblast Migration Periventricular and White Matter (Band) Heterotopias
Heterotopias suggest a migration defect whereby the migrating neurons exit their radial glia before reaching the normal cortical mantle Peri-ventricular stroke Polymicrogyria Lissencephaly
Band Heterotopia Agenesis of corpus callosum Heterotopias suggest a migration defect whereby the migrating neurons exit their radial glia before reaching the normal cortical mantle Cerebral Cortex Development
Week 40
Week 14: cortex is smooth and does not cover diencephalon. Week 26, the cortex has expanded greatly and major sulci begin to form Week 30, most major sulci have formed and the cortex continues to expand and convolute; forming many of the adult sulci and gyri. Postnatal Cerebral Development
Full maturity – not until late adolescence - mid 20s Brain volume quadruples between birth & adulthood due to: Synaptogenesis Dendritic growth Myelination
• Myelination • Adult Neurogenesis • Continuous synaptogenesis • Synapse Elimination • Experience/Activity-dependent processes • End of PART I