Nervous system biom3040 L13-14

Normal CNS Development

• Normal central nervous system (CNS) development includes neurulation, regionalization, proliferation/migration, and connection/selection.

Neurulation

• Neurulation involves the induction of the neural plate and the formation of the neural tube.

Regionalization

• Regionalization specifies that the brain develops rostrally (anteriorly) while the spinal cord develops caudally (posteriorly).

Proliferation and Migration

• Proliferation occurs within the brain, supporting growth.
• Neural crest cells migrate to form the peripheral nervous system (PNS).

Connection and Selection

• Connection and selection involves axon outgrowth and synapse formation, processes that occur after cells are specified by type and properly positioned.

Proliferation within the Neural Tube

• The orientation of the mitotic spindle determines the fate of daughter cells during proliferation in the neural tube.
• If the metaphase plate is perpendicular to the apical surface, daughter cells migrate back towards the outer side, undergo DNA synthesis, and become neural cells.
• If the metaphase plate is parallel to the apical surface, daughter cells progress to the next stage in the neural lineage, producing more differentiated cells.

Cell Lineages in the Developing CNS

• Most CNS cells originate from multipotential stem cells in the neuroepithelium.
• These stem cells undergo mitotic divisions and become bipotential progenitor cells.
• Bipotential cells differentiate into either neuronal or glial progenitor cells.
• Neuregulin expression marks the proliferating state of neurogenesis and is downregulated during differentiation.

Neuron-Glial Cell Switch

• The neuron glial cell switch involves multiple factors.
• Downregulation of neuregulin.
• Secretion of neurogenesis inhibitory cytokines.
• Changes in the growth factor environment.
• Activation of progliogenic transcription factors (nuclear factor I-A, SOX-9, OLIG-2).
• Activation of the Notch signaling pathway.

Layers of the Early Neural Tube

• Layers include the ventricular, mantle/intermediate, and marginal layers.

Ventricular Layer

• The ventricular layer (green) is where cells line the central canal and proliferate, giving rise to neuroblasts and glioblasts.
• It is the layer of cells closest to the lumen of the neural tube and is epithelial.

Mantle/Intermediate Layer

• The mantle/intermediate layer (pink) forms the gray matter of the CNS.
• It is divided into the alar and basal plates.
• This zone contains cell bodies of neuroblasts.

Marginal Layer

• The marginal layer (blue) contains axons and neurons within the mantle and forms the white matter of the CNS.
• It contains neuronal processes, but not neuronal cell bodies.

Sensory and Motor Regions of the Spinal Cord

• The neural tube caudal to the fourth pair of somites develops into the spinal cord.
• The sulcus limitans divides the spinal cord into a dorsal alar plate and a ventral basal plate.
• The right and left alar plates are connected dorsally by a roof plate.
• The left and right basal plates are connected ventrally by a floor plate.
• The alar plate is dorsal and associated with sensory functions, forming the dorsal horn.
• The basal plate is ventral, associated with ventral motor roots of spinal nerves, and forms the ventral horn.

Establishment of the Nervous System

• Induction of the nervous system results in the formation of a thickened ectodermal neural plate overlying the notochord.
• Chordamesoderm inductive signal specifies ectoderm as neural.
• Neural induction involves suppression of induction of epidermal fate.
• Neural inducers, noggin and chordin, block the role of BMP-4, allowing the dorsal ectoderm to form neural tissue.

Signaling in the Early CNS

• Signals from Shh in the notochord induce the floor plate.
• BMP-4 and BMP-7 from the ectoderm induce Snail-2 expression and maintain Pax-3 and Pax-7.
• Shh produced by the floor plate induces motoneurons and suppresses dorsal Pax genes (3,7) in the ventral half of the neural tube.
• The roof plate expresses Wnt and BMPs, exerting a dorsalizing influence.

Migration of Neural Crest Cells

• Neural crest cells migrate to form:
  • Dorsal root ganglia
  • Autonomic ganglia
  • Schwann cells
  • Melanocytes
  • Odontoblasts
  • Mesenchyme of pharyngeal arches

Motor Axons

• Motor axons derive from the basal plate and grow out from motor neuroblasts.

Sensory Neurons

• Peripheral processes project toward target muscles and skin.
• Central processes project toward the dorsal horn of spinal cord.

Summary of Spinal Cord Development

• The alar plate (AP) and basal plate (BP) of the embryonic spinal cord develop into sensory and motor regions of the mature spinal cord.
• The central canal of the spinal cord is the remnant of the cavity of the neural tube.

Formation and Segmentation of the Spinal Cord

• The segmentation of the spinal cord is imposed by signals from the paraxial mesoderm.
• The most caudal part of the neural plate possesses stem cell-like properties.
• FGF-8 secreted from the adjacent presomitic mesoderm induces these cells to proliferate.
• Retinoic acid produced by somites stimulates these cells to differentiate into neurons.

Formation of the 3-Part Brain

• Recognizable spinal cord and brain are visible by the end of neurulation.
• Flexures shape the early nervous system.
  • Cervical
  • Cephalic
  • Pontine

The 3-Part Brain

• This consists of the forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon).

Brain Development

• The 3-part brain develops into 5 parts by 5 weeks via secondary vesicles.

Segmentation of the Prosencephalon (Forebrain)

• The telencephalon forms cerebral hemispheres.
• The diencephalon forms optic and thalamic tissues.
• The mesencephalon does not subdivide/segment.

Segmentation of the Hindbrain (Rhombencephalon)

• Rhombomeres are subsegments of the rhombencephalon that determine the pattern of development/maturation.
• The rhombencephalon consists of the metencephalon (cerebellum and pons) and the myelencephalon (medulla).

Signalling Centers Regionalize the Early Embryonic Brain

• The notochord sends signals to the neural tube to divide differential parts.
• The neural tube receives induction signals from the notochord and head organizing regions during gastrulation.
• Otx-2 and Gbx-2 transcription factor expression marks the division between forebrain/midbrain and hindbrain/spinal cord.
  • Otx-2 is in the forebrain/midbrain region
  • Gbx-2 is in the hindbrain region

Nerve Cell Differentiation

• Neurons grow by extending "growth cones".
• The growth cone moves by extending a ruffled membrane and filopodia.
• The growth cone is rich in actin filaments and senses the environment, responding to positive and negative chemotactic signals.

Neurotrophic Factors

• Neurotrophic factors act on neurons to support differentiation, growth, and survival.
• The dermomyotome releases at least 3 neurotrophic factors.

Mechanism of Neurite Outgrowth

• Outgrowth is guided by chemoattraction (netrins increase cAMP/cGMP), contact attraction (cell adhesion proteins, laminin, fibronectin promote adhesion), chemorepulsion (semaphorins decrease second messengers), and contact repulsion.

Development of Neural Formation

• During the first 5 weeks of embryological development, there is no evidence of neural activity.
• By week 6, reflex activity can be seen.
• Spontaneous uncoordinated movements occur by week 7.
• More coordinated movements develop as motor tracts and reflex arcs are established.

CNS Development

• The neural plate (neuroectoderm) becomes the neural tube, which gives rise to the brain and spinal cord.
• The basal plate gives rise to the preganglionic sympathetic neurons.
• Neural crest cells give rise to postganglionic sympathetic neurons and chromaffin cells of adrenal gland medulla.

PNS Development

• Peripheral nervous system (PNS) is derived from:
• neural crest cells
• the neural tube (preganglionic autonomic nerves and all motor neurons/nerves that innervate skeletal muscles)
• the mesoderm (dura mater and connective tissue of peripheral nerves)
• The basal plate gives rise to preganglionic parasympathetic neurons.
• Neural crest cells give rise to postganglionic parasympathetic neurons.

Sympathetic vs Parasympathetic

• Sympathetic has a short preganglionic neuron and a long postganglionic neuron.
• Parasympathetic has a long preganglionic neuron and a short postganglionic neuron.

Neural Crest Cells

• Neural crest cells form a wide range of cell types and structures.
• They are considered the fourth germ layer.
• Arise from cells located along the lateral border of the neural plate during neurulation.
• They undergo epithelial-mesenchymal transition.
• They are multipotential.
• They undergo prolific migration throughout the embryo.
• They differentiate into a wide array of adult cells and structures.

Neural Crest Cell Induction

• The formation of the neural crest begins in gastrulation, with gradients of BMPs, Wnt, and FGF leading to the neural plate.
• Cells at the border of the neural plate activate genes for transcription factors.
  • Msx-1, Msx-2, Dlx-5, Pax3, Pax7 specify the neural plate border.
  • Foxd-3, Sox-10 and Ets-1 specify the neural crest progenitor cells.

BMPs Role

• The role of BMP is complex and associated with a concentration gradient along the ectodermal layer during neurulation.
• Cells within the neural plate are exposed to the lowest concentrations of BMP because of local inhibitory actions of noggin and chordin.
• Cells at the border of the neural plate are exposed to intermediate levels of BMP forming neural crest precursor cells.

Induction of the Neural Crest

• Separation of the neural crest from the lateral edge of the neural plate and tube is called delamination.
• BMP, Wnt, and FGF-8 are inductive signals.
• Responding to inductive signals- cells at the border of the neural plate express genes for transcription factors [Msx-1, Msx-2; Pax-3, Pax-7; Gbx-2.

Transcription Factors

• At least 3 genes are involved in the separation of neural crest cells.
  • Transcription factors- Fox D3, snail 1 and slug (snail 2).
• Overexpression of:
  • FoxD3 can cause delamination of the neural tube.
  • Slug only leads to delamination of head neural crest.

Changes in Cadherin Expression

• Under the influence of snail-1 and snail-2 [slug]- profile of cadherins produced by the neural crest precursors changes.
• Changes from Type I cadherins (N-cad, E-cad) which are very adhesive to Type II cadherins, which are less adhesive.
• Type I cadherins remains down-regulated during migration.

Factors That Guide Neural Crest Cells

• Fibronectin/laminin (proteins of ECM) and Neuregulins (promote of the nerve growth factor family) promote movement.
• Ephrins and Semaphorins make cells stick where they are.
• All 4 work together to affect the neural crest cells.

BMP's and Wnt6

• FoxD3 is important for the specification of ectodermal cells as neural crest cells.
• Slug (snail-2):
  • Activated factors that dissociate the tight junctions (loss of N-cadherin).
  • Important for neural crest cells to leave the epithelium and migrate.
• RhoB:
  • Promotes actin polmerization into microfilaments and their attachment to the cell membrane.
  • Important for establishing cytoskeletal conditions that promote migration.

Major Divisions of the Neural Crest

• Cranial (anterior) neural crest: This is a major component of the cephalic region of the embryo and forms structures in the face and neck.

Circumpharyngeal Neural Crest

• Migrate toward the gut and heart:
  • Vagal NCS: Submucosal and myenteric plexi (uses)
  • Cardiac NCS: semilunar valves, cranial nerve, Schwann cells

Trunk Neural Crest

• This extends from the 6th somite to the most caudal somites.
• • This contributes to melanocytes, sensory neurons and gila of the trunk, adrenal medulla.

Migratory Routes of Trunk Neural Crest Cells

• Sympathoadernal pathway: crest cells that migrate first and are capable of forming many types of cells.
• Ventrolateral pathway: next wave of crest cell migration that can only form a few cell types.
• Dorsolateral pathway: last crest cells to migrate, can only become pigment cells (melanocytes).

Cardiac Neural Crest

• This is responsible for some of the components of the heart (aorta and pulmonary arteries).
  • Neural crest cells give rise to:
    • neurons
    • cartilage
    • connective tissue
• They generate the endothelium of the aortic arch arteries and the septum between the aorta and pulmonary arteries.

Cell Differentiation

• Neural crest cells are pluripotent.
• They are able to make all the neurotransmitters needed.
• Once a final destination is established they make the neurotransmitter required.
• Final differentiation is directed by their final environment.

Neural Crest Abnormalities

• Abnormal migration, differentiation, division, or survival of neural crest cells.

Waardenburg Syndrome (Pax-3 mutations)

• Type I and III are caused by Pax-3 mutations, involving pigmentation defects, deafness, cleft palate, and ocular hypertelorism.
• Type I involves hypoplasia of limb muscles due to Pax-3 myogenic cells migrating into limb buds from the somites.
• Hyperpigmented skin and hair (piebaldism) are associated with mutations of the KIT gene.

Neurofibromatosis

• Groups of three conditions in which tumors grow in the nervous system.

NF1

• Light brown spots, freckles, small bumps within the nerves, and scoliosis and peripheral nerve neurofibromas.

NF2

• Involves hearing loss, cataracts, flesh colored skin flaps, and muscle wasting.
• Causes Schwann cell tumors and is the most serious type of neurofibromatosis.

Schwannomatosis

• Neural crest cells are the precursors that cause mutations to Schwann cells.
• All of these condidtions are caused by genetic mutation. -- 50% inherited, 50% developmental problems.