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(III. Differentiation and Architecture of the CNS, IV. Neural Crest Cells…
III. Differentiation and Architecture of the CNS
Anterior-Posterior Axis
Early neural tube balloons into three primary vesicles in the anterior region:
Forebrain (prosencephalon)
Midbrain (mesencephalon)
Hindbrain (rhombencephalon)
The rhombencephalon develops rhombomeres (periodic swellings) that specify where certain nerves originate. Rhombomeres are separate developmental "territories" with distinct fates.
Specification is regulated primarily by Hox genes (hindbrain) and Otx (brain).
Dorsal-Ventral Axis
Dorsal region: Receives input from sensory neurons. Patterning is imposed by the epidermis.
Dorsal Fates: Established by TGF- $\beta$ superfamily proteins (BMP4, BMP7, dorsalin, activin). The epidermis induces BMP4 expression in the roof plate cells.
Ventral region: Motor neurons reside. Patterning is induced by the notochord.
Ventral Agent: Sonic hedgehog protein, probably originating from the notochord, establishes a gradient that determines different cell types.
Middle region: Contains interneurons that relay information.
Tissue Architecture
Neurons are organized into layers (cortices) and clusters (nuclei).
Original neuroepithelium is the Ventricular Zone (or germinal epithelium).
As cells divide and migrate, they form the Mantle Zone (second layer).
Mantle zone cells differentiate into neurons and glia and are often referred to as gray matter.
Axons grow away from the lumen, forming the cell-poor Marginal Zone.
Axons in the marginal zone are covered in myelin sheaths, forming white matter.
Adult Neural Stem Cells
Environmental stimulation can increase the number of new neurons in the mammalian brain.
Stem cells are located in the ependyma (the former ventricular layer).
IV. Neural Crest Cells (NCCs)
Overview
Sometimes called the "fourth germ layer".
Originate at the dorsalmost region of the neural tube.
Are pluripotent; a single cell can differentiate into various types depending on location.
Derivatives (Generated cell types)
Neurons and glial cells (of sensory, sympathetic, and parasympathetic nervous systems)
Epinephrine-producing (medulla) cells of the adrenal gland
Pigment-containing cells of the epidermis (melanocytes)
Skeletal and connective tissue components of the head
Functional Domains
Cranial (Cephalic) NCC: Migrates dorsolaterally to produce craniofacial mesenchyme, differentiating into cartilage and bone (unlike trunk NCCs), cranial neurons, and connective tissues of the face. Cells from rhombomeres 1 and 2 form jawbones.
Trunk NCC: Disperses after neural tube closure.
Dorsolateral pathway: Becomes melanocytes.
Ventral pathway: Becomes sensory (dorsal root) and sympathetic neurons, adrenomedullary cells, and Schwann cells.
Vagal and Sacral NCC: Generates the parasympathetic (enteric) ganglia of the gut.
Cardiac NCC: Extends from the first to the third somites. Generates endothelium of the aortic arch arteries and the septum. Expresses the transcription factor Pax3 (mutations cause failure of aorta/pulmonary artery separation).
Migration and Differentiation
Initiation: BMP 4 and 7 induce Slug protein (dissociates tight junctions and N-cadherin loss) and RhoB protein (establishes cytoskeletal conditions for migration).
Guidance (Extracellular Matrix): Migration is promoted by fibronectin, laminin, tenascin, and collagen. Migration is impeded or paths are specified by ephrin proteins.
Final Differentiation: Determined by the environment to which they migrate. For example, LIF (Leukemia Inhibition Factor) and BMP2 can influence the conversion of adrenergic neurons into cholinergic neurons.
V. Neuronal Specification and Axonal Specificity
Neurogenesis Stages (Includes):
Induction and patterning of a neurogenic region.
Birth and migration of neurons and glia.
Guidance of axonal growth cones to specific targets.
Formation of synaptic connections.
Axonal Growth
Axons have their own locomotory apparatus residing in the growth cone.
The initial pathway is determined by the environment.
Motor neuron specificity is regulated by the cell's age when it last divides.
Guidance Mechanisms
Substrates (Adhesion): Extracellular environments provide navigational information.
Haptotaxis: Directs axons via a gradient of increasingly adhesive molecules.
Substrates include laminin, N-CAM, L1, or NrCAM.
Diffusible Molecules
Attraction: Commissural neurons are triggered by diffusible factors to send axons toward the ventral floor plate.
Repulsion: Slit protein (secreted at the midline) prevents most neurons from crossing. The receptor for Slit is the Roundabout (Robo) protein.
Target Selection and Survival
Neurotrophins: Chemotactic factors produced by target cells (e.g., NGF, BDNF, NT-3, NT-4/5). They promote the growth of some axons while inhibiting others.
Synapse Formation: Axon terminals accumulate synaptic vesicles. Muscle-derived laminin specifically binds motor neuron growth cones and may act as a "stop signal". N-cadherin stabilizes neuron-to-neuron synapses.
Survival: Over half the neurons may die during normal development even after successfully reaching their targets. The target tissue regulates the number of innervating axons by limiting the supply of neurotrophins.
I. Overall Structure and Cell Types
Central Nervous System (CNS)
Consists of the brain and spinal cord.
Formed from the neural plate of the early embryo.
Peripheral Nervous System (PNS)
Consists of the cranial, spinal, and autonomic nerves and associated ganglia.
Formed from the neural crest, epidermal placodes, and axons growing from cell bodies in the CNS.
Neurons
Have numerous dendrites (receiving input).
Have one axon (emitting signals).
Human brain contains around $10^{11}$ neurons, each forming synapses with approximately $10^3$ others.
Connectivity is achieved during embryonic development.
II. Neurulation (Formation of the Neural Tube)
Two Major Ways of Formation
Primary Neurulation
Cells surrounding the neural plate cause plate cells to proliferate, invaginate, and pinch off to form a hollow tube.
Process begins when underlying dorsal mesoderm signals ectodermal cells to elongate into the columnar neural plate.
Bending involves the formation of hinge regions.
Medial Hinge Point (MHP) cells: Anchored to the notochord; decrease height and become wedge-shaped.
Dorsolateral Hinge Points (DLHPs): Form furrows near the connection with the ectoderm. Involved microtubules (elongation) and microfilaments (apical constriction/wedge formation).
Closure: Paired neural folds are brought together and merge at the dorsal midline.
Cell Adhesion: Separation is mediated by changes from E-cadherin (original) to N-cadherin and NCAM.
Secondary Neurulation
Arises from a solid cord of cells that sinks into the embryo and subsequently hollows out (cavitates).
Seen in the neural tube of the lumbar and tail vertebrae (frogs and chicks).
Can be viewed as a continuation of gastrulation.
Regionalization and Structure
Closure does not occur simultaneously; cephalic (head) region is often advanced while the caudal (tail) region is still undergoing gastrulation.
Swellings and constrictions define brain compartments.
Open ends are the anterior neuropore and posterior neuropore.
Neural Tube Defects (NTDs)
Failure to close various parts of the neural tube.
Spina Bifida: Failure to close posterior neural tube regions (around day 27).
Anencephaly: Failure to close anterior neural tube regions; results in the forebrain remaining in contact with amniotic fluid and degenerating (lethal condition).
Prevention: Requires genes (e.g., Pax3) and dietary factors such as folic acid (folate), which could prevent an estimated 50% of human NTDs.