Biology 4361 Developmental Biology Gilbert Ch. 12. The Emergence of the Ectoderm: Central Nervous System and Epidermis November 30, 2006

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1 Biology 4361 Developmental Biology Gilbert Ch. 12. The Emergence of the Ectoderm: Central Nervous System and Epidermis November 30, 2006 Establishing the Neural Cells - neural plate - portion of the dorsal ectoderm specified to become neural ectoderm - distinguishable by columnar appearance of cells - neurulation - process of forming the neural tube - neural tube forms the brain anteriorly and the spinal cord posteriorly - neurula - embryonic stage of neural development neural cells become specified though their interactions with other cells - pluripotent cells of the epiblast or blastula become neural precursor cells - neuroblasts - stages include: - competence - cells can become neuroblasts with proper signals - specification - cells have received signals to become neuroblasts, but fate can be altered by other signals (e.g. repressive or inhibitory signals) - commitment (or determination) - neuroblasts have entered differentiation pathway and will become neurons even in the presence of inhibitory signals - differentiation - neuroblasts leave the mitotic cycle ; express genes characteristic of neurons Formation of the Neural Tube - two ways of converting neural plate into neural tube: - primary neurulation - neural plate cells form hollow tube - secondary neurulation - neural plate cells form solid cord; subsequently hollows out - in general, anterior portion of neural tube is made by primary neurulation; posterior by secondary neurulation Primary neurulation - ectoderm can be divided into three sections: - internally positioned neural tube - forms brain and spinal cord - externally positioned epidermis - forms skin - neural crest cells - form in the region connecting the neural tube and epidermis - migrate to new locations - generate peripheral neurons, glia, pigment cells, others - primary neurulation appears similar in all vertebrates: - summary example - amphibians: - shortly after neural plate formation, edges thicken; move upward to form neural folds

2 - U-shaped neural groove appears in center of plate - folds migrate to the midline of the embryo - fuse and form tube beneath the overlying epidermis Details: four distinct, but spatially and temporally overlapping stages: - formation of the neural plate - shaping of the neural plate - bending of the neural a plate to form the neural groove - closure of the neural groove to form the neural tube FORMATION AND SHAPING OF THE NEURAL PLATE - dorsal mesoderm and pharyngeal endoderm in the head region signal ectoderm above to elongate into columnar neural plate cells - as much as 50% of ectoderm is included in neural plate - neural plate lengthens along the AP axis - mechanism: convergent extension; intercalating several layers into a few layers - also, preferential division along rostral-caudal (beak-tail; anterior-posterior) axis BENDING OF THE NEURAL PLATE - hinge regions form; - in birds and mammals, cells at midpoint of neural plate form the medial hinge point (MHP) cells - MHP cells anchor to the notochord - notochord induces MHP cells to decrease height and become wedge-shaped - dorsolateral hinge points (DLHPs) - two hinge regions form furrows near the connection of the neural plate with the remainder of the ectoderm - anchored to surface ectoderm - decrease height, become wedge shaped - after initial furrowing of the neural plate, plate bends around hinge regions - hinges act as pivots that direct the rotation of the cells around it - also, surface ectoderm of chick embryo pushes toward the midline - neural plate anchored to underlying mesoderm - motive force by ectoderm produces inward folding movement CLOSURE OF THE NEURAL TUBE - paired neural folds brought together; adhere; merge - closure is not simultaneous or continuous throughout the tube; e.g. in vertebrates induction of the head starts before induction in the posterior regions - 24 h chick - neurulation in cephalic region is well advanced, while caudal region is still undergoing gastrulation

3 - two open ends of the neural tube are: - anterior neuropore - posterior neuropore - mammals - neural tube closure in initiated ast several places along the A-P axis - humans - probably 3 closure initiation sites - neural tube defects are caused by failure of closure at a given site - in humans, ~ 1/1000 births have some for of NTD - spina bifida - failure to close the posterior neuropore (~ d 27) - severity depends on how much spinal cord is exposed - anencephaly - failure to close the anterior neuropore - forebrain exposed to amnionic fluid and subsequently degenerates - craniorachischisis failure of entire neural tube to close - neural tube forms a closed cylinder that separates from the surface ectoderm - separation mediated by the expression of different cell adhesion molecules - cells that become neural tube originally express E-cadherin (epidermal); but stop expression and shift to N-cadherin (N-CAM) - as a result, neural tube and epidermal cells no longer adhere to each other - neural tube closure (humans) is dependent on mixture of intrinsic (i.e. gene products) and extrinsic (i.e. nutritional/environmental) factors - requires Pax3, Sonic hedgehog, openbrain - dietary factors, e.g. cholesterol, folic acid (folate, vitamin B 12) also essential - role of folate not completely understood, but folate receptors appear to be present on the dorsalmost regions of mouse neural tube - natural antibodies to folate receptor have been associated with neural tube defects in humans - also plant-derived or anthropogenic teratogens may play a role Secondary neurulation - segregation of cells from prospective epidermis and prospective gut tissue form prospective medullary cord beneath the surface ectoderm - followed by cavitation of central portion of cored into several hollow spaces - cavities coalesce into single cavity Differentiation of the Neural Tube Differentiation occurs simultaneously on three different levels: - gross anatomical level: neural tube and its lumen bulge and constrict to form the chambers of the brain and spinal cord - tissue level: cell populations withing the wall of the neural tube rearrange themselves to form the different functional regions of the brain and spinal cord - cellular level: neuroepithelial cells differentiate into numerous types of nerve cells (neurons) and supportive cells (glia)

4 The anterior-posterior axis - early neural tube is a straight structure - anterior of the tube balloons into three primary vesicles - forebrain (prosencephalon) - secondary bulges - optic vesicles, form by the time of posterior neural tube close - midbrain (mesencephalon) - hindbrain (rhombencephalon) - prosencephalon subdivides into - telencephalon (anterior) - will form cerebrum - diencephalon (caudal) - will form optic vesicles - thalamus - receives neural input from retina - hypothalamus - neural input - mesencephalon - not subdivided - lumen forms cerebral aqueduct - rhombencephalon subdivides into: - metencephalon (anterior) - cerebellum - coordinates movement, posture, balance - myelencephalon (posterior) - forms medulla oblongata - pain related to head and neck, auditory connections, tongue movement, balance, respiratory, gastrointestinal, cardiovascular movements - also, rhombencephalon develops a segmental pattern that specifies places where certain nerves originate - rhombomeres originate the cranial nerves - lumen of neural tube (brain/spinal cord) is inflated by osmotic pressure caused by Na + /K + ATPase - also, production of cerebrospinal fluid helps fill the lumen - regional cell proliferation The dorsal-ventral axis - the neural tube is polarized along the dorsal-ventral axis - dorsal region neurons receive input from sensory neurons - ventral region sends out motor neurons - ventral patten established by the notochord - Sonic hedgehog protein - dorsal pattern established by the epidermis - TGF-â proteins

5 - in both cases (i.e. dorsal and ventral), secondary signaling centers are established in the respective neural tube cells - Shh secreted from the notochord induced the medial hinge cells to become the floor plate of the neural tube - floor plate cells also secrete Shh - creates an Shh gradient; highest at the most ventral part of the tube - dorsal fates established by TGF-â proteins; esp. BMP4, and 7, dorsalin, activin; establishes a secondary center: roof plate - roof plate induces a cascade of TGF-â proteins in adjacent cells - paracrine factors interact to instruct the synthesis of different transcription factors along the D-V axis of the neural tube Tissue Architecture of the Central Nervous System Brain neurons are organized into layers (cortices) and clusters (nuclei) Neural tube is composed of germinal epithelium - rapidly dividing cells; one layer thick - mitosis occurs on the luminal side of the epithelium - as the cells age, the nucleus moves from the luminal side to the adluminal side - when cells of the germinal neuroepithelium are ready to generate neurons (instead of more neural stem cells, one of the two daughter cells remains in the epithelium while the other becomes detached - the cell remaining in the luminal surface continues as a stem cell - second cells migrates and differentiates - this vertical division is the last time that particular cell will divide: therefore, the time of division is the cell s birthday - different types of neurons and glial cells have birthdays at different times - cells with the earliest birthdays migrate the shortest distances - cells with the latest birthdays migrate the longest distances - therefore, younger neurons migrate through older neural layers - subsequent differentiation depends on the positions the neurons occupy once outside of the germinal neuroepithelium Spinal cord and medulla organization - cells adjacent to the lumen continue to divide - migrating cells form a second layer around the original neural tube - new layer called the mantle (or intermediate) zone - germinal epithelium now called the ventricular zone (later, the ependyma) - mantle zone cells differentiate into both neurons and glia - neurons make connections among themselves and send axons away from the lumen;

6 create a cell-poor marginal zone - eventually, glial cells cover many of the axons in the marginal zone with myelin sheathes = whitish appearance - hence, the axonal marginal zone is referred to as white matter - mantle zone, containing cell bodies, referred to as gray matter - in the spinal cord and medulla, the basic three-zone patter: ventricular (ependymal), mantle, marginal layer - retained throughout development - in cross-section, the gray matter gradually takes on a butterfly-shaped structure surrounded by white matter - both become surrounded by connective tissue - as the neural tube matures, a longitudinal groove, the sulcus limitans divides into dorsal and ventral halves - dorsal portion - receives input from sensory neurons - ventral portion - involved with various motor functions Cerebellar organization Brain organization is different from spinal cord organization - cerebellar organization: - some neuronal precursors enter the marginal zone to form clusters of neurons called nuclei (not the same a the cell nucleus) - each nucleus works as a functional unit, serving as a relay station between the outer layers of the cerebellum and other parts of the grain - other neuronal precursors migrate away from germinal epithelium - cerebellar neuroblasts migrate to the outer surface of the developing cerebellum and form a new germinal zone: the external granule layer - neuroblast at the outer boundary of the eternal granule layer proliferate - come in contact with BMP factors - BMPs specify neurons to become granule neurons - granule neurons migrate back toward ventricular zone; produce an internal granule layer - ventricular zone neuroblasts generate variety of neurons and glial cells - including Purkinje neurons - Purkinje neurons produce Shh; sustains division of granule neuron precursors in the external granule layer - each Purkinje neuron has an enormous dendritic arbor - may form as many as 100,000 connections (synapses) with other neurons - glial cells guide young neurons to positions within the brain - neurons ride the glial monorail Cerebral organization

7 The Unique Development of the Human Brain Adult neural stem cells Differentiation of Neurons Human brain - 10 neurons; 10 glial cells - neuroepithelial cells of neural tube give rise to three main cell types - ventricular (ependymal) cells - remain integral components of the neural tube lining - secrete cerebrospinal fluid - precursors of neurons - precursors of glial cells - aid in the construction of the nervous system - provide insulation around the neurons - may be important in memory storage - a given neuroepithelial cell may give rise to both neurons and glial cells - dendrites: fine, branching extensions of the neuron used to pick up electrical impulses from other cells - few dendrites in cortical neurons at birth - massive increase in the first year - avg. cortical neuron connects with 10k other neural cells - axon (a.k.a. neurite): continuous extension of the nerve cell body (soma) - nerve outgrowth (axon formation) is led by the tip of the axon: the growth cone - growth cone does not proceed in a straight line; feels its way along the substrate - moves by elongation of and contraction of pointed filopodia - microspikes - contain microfilaments oriented parallel to the long axis of the axon - microspikes attach to the surface and pull the rest of the cell forward - microspikes also have a sensory function - each microspike samples the microenvironment and sends signals back to the soma - axons are wrapped in insulating layers of glial cells - central nervous system: oligodendrocytes wrap themselves around the developing axon - produces a specialized membrane called the myelin sheath - peripheral nervous system: Schwann cells - axons control the thickness of myelin sheath - demyelination of nerve fibers is associates with convulsions, paralysis, certain debilitating afflictions; e.g. multiple sclerosis - axons are specialized for secreting specific chemical neurotransmitters across the small gaps that separate the axon of a neuron from the surface of its target cell

8 - synaptic cleft Development of the Vertebrate Eye The major sensory organs of the head develop from interaction of the neural tube with a series of epidermal thickening called the cranial ectodermal placodes - most form neurons and sensory epithelia - olfactory placodes - form nasal epithelium and ganglia for olfactory nerves - otic placodes - invaginate to form the inner ear labyrinth - lens placodes - forms lens The dynamics of optic development Eye induction: - at gastrulation, involuting endoderm and mesoderm interact with adjacent prospective head ectoderm to give head ectoderm a lens-forming bias - optic vesicle activates lens formation and ensures positioning of lens in relation to retina - optic vesicle extends for the diencephalon - meets the head ectoderm - induces lens placode - placode invaginates to form lens - optic vesicle invaginates to form optic cup - cell in outer layer differentiate to produce melanin pigment - becomes pigmented retina - cells in inner layer proliferate rapidly; generate variety of glia, ganglion cells, interneurons (connecting neurons), and light-sensitive photoreceptor cells - collectively known as the neural retina - retinal ganglion cells are neurons whose axons send electrical impulses to the brain - retinal ganglion axons meet at the base of the eye; travel down the optic stalk - becomes the optic nerve Neural retina differentiation Lens and cornea differentiation The Epidermis and the Origin of Cutaneous Structures