Neuroanatomy(9-12) Development

Ectodermal cells

Neural tube - CNS

Neural crest - these are multipotent, migratory cells giving rise to a diverse cell lineage including melanocytes, craniofacial cartilage & bone, smooth muscle, peripheral & enteric neurons and glia

BMP influences ectodermal cells by supressing neural differentiation and promoting fomation of epidermal tissues

It provides an example of how single molecules influence very different tissues such as bone and nervous system

Diffusible signal proteins from Hendsen's node (Chordin & Noggin) block the action of BMP and allow for a selection of ectodermal cells to form the neural plate

Anencephaly - rostral nonclosure

Spina bifida - caudal nonclosure

A conserved stretch of DNA is termed "homeobox" which enocdes a sequence of 60 amino acids that recognize and bind to specific DNA sequences in a series of subordinate genes

Retinoic acid

Hensen's node releases retinoic acid, establishes a gradient along the short length of the embryo that contributes to the orderly anterior-posterior sequence of Hox gene expression in the hindbrain

emx - genetic abnormalities of emx develop schizencephaly (deep crevices in cortex)

otx - genetic defects w/ otx develop epilepsy

Sonic hedgehog protein is produced by the notochord and later by the floor plate.

High levels of sonic hedgehog protein induce cells of the nerual tube to become floor plate cells

BMP, secreted by ectodermal cells dorsal to developing spinal cord, induces the specification of cells that lie in the dorsal horn

A mutation in the homeotic gene controling eyes.

Prosencephalon, Mesencephalon, Rhombencephalon

Prosencephalon - Telencephalon & Diencephalon

Mesencephalon - Midbrain

Rhombencephalon - Metencephalon & Myelencephalon

Sonic hedghog protein induce cells of the neural tube to become floor plate cells. BMP induces specification of cells that lie in dorsal horn. Retinoic acid acts to specify longitudinal gradients

Radial glial cells maintain contact w/ both the ventricular and pial surfaces of the neural tube.

Neurons move along this scaffolding of radial glial cells to reach their appropriate positions in the cortex.

glycoprotein astotactin & the extracellular matix adhesion molecule receptor integrin

Cajal-Retzius cells express the reeler gene which produces "reelin", an extracellular matrix glycoprotein. Cortical cells recognize reelin as a signal to get off the glial monorail and take up their final position in the cortex.

Neurons move along their radial glial cells to reach appropriate position in cortex starting from the ventricular zone to the outer pial surface.

Neurons expressing gonadotropin-releasing hormone (GnRH) migrate into the CNS, moving from the olfactory pit (ectodermal derived (placode) giving rise to nasal epithelium) into the hypothalamus along a previously established axon tract.

A neuronal cells environment influences its commitment to a specific function.

The neuronal location, where they come to rest and which targets they are matched with will determine which neurotransmitter is released.

Leukemia inhibitory factor (LIF) is a peptide released by muscle cells which cause the change in phenotype.

Such changes as neural crest cells originally noradrenergic becoming cholinergic when co-cultured w/ heart muscle which release LIF causing the change in phenotype.

LIF also induces differentiation of cells in the immune system

PMP-22 is a peripheral myelin protein, essential for the layers of Schwann cell membranes to wrap and seal themselves around developing axons.

Schwann cells on their own make PMP-22 but break it down unless neurons are available, at which time the Schwann cells express PMP-22 in their membranes which fuse to form myelin.

A "Trembler" mouse has a genetic disorder where myelin fails to form properly.

If we take a nerve from a normal mouse is implanted into a trembler mouse, that normal nerve begins to mylinate other nerves and the opposite applies to a trembler nerve being placed in a normal mouse where it doesn't mylinate. Thus the defect is in the Schwann cells and not the axons of the Trembler mouse

Charcot Marie Tooth Disease has defective PMP-22 and peripheral myelin fails to form properly.

The cause being a substitution of glycine to aspartate

The material surrounding neurons and satellite cells contains large molecules, Laminin, which promote neurite outgrowth. Laminin is present along pathways that axons follow as they extend their processes in the developing nervous system and it is synthesized by Schwann cells particularly after injury. Specific antibodies against laminin block neurite extension and outgrowth.

Diffusible molecule - Netrin

Extracellular matrix molecule - Laminin

The tip of a growing axon is enlarged (growth cone) which extends and moves to contact other cells and the substrate its passing through. Receptors on axon surface interact with specific diffusible molecules of substrate. Some growth cones release enzymes to help clear a path and change the substrate. Diffusible molecules, Netrin, released by cells along the pathway may also attract the growing axon.

Both sympathetic and many sensory neurons require NGF for growth & survival. NGF is taken up by nerve terminals , actively transported back to soma, where it regulates synthesis of norepinephrine by enducing tyrosine hydroxylase & dopamine b-hydroxylase.
The high affinity NGF receptor, TrkA (tyrosine kinase A), is normally found only on neurons but was first discovered in human colon carcinoma as product of trk oncogene.
After NGF binds to TrkA, tyrosine phosphorylation activates phospholipase C, phosphatidylinositol-3-kinase & MAP kinase

TrkA receptors bind NGF
TrKB receptors bind BDNF

Nerve Growth Factor (NGF) and Brain-derived Neurotrophic Factor (BDNF)

Sensory neurons, neural crest cells & sensory neurons of the dorsal root ganglion require BDNF or NT-3 for proliferation, differentiation, and survival. Neurotrophins at such early stages appear to be provided by the neurons themselves and mesenchymal tissues through which the axons grow. After axons reach targets, sensory neurons begin to express NGF receptors and become dependent on target derived NGF for survival.

Neurotrophins have also shown to influence efficacy of synaptic transmission within cortex and maintenance of LTP in hippocampus

Apoptosis is programed cell death which in relevance to neurodevelopment seems to provide a numerical matching between neurons and targets where cells maybe competing for vital growth factors.

Axons of the retina sort themselves out along ant.-post. axis based on repulsize interactions w/ Eph (ephrin - receptor tyrosine kinases):

Axons from ganglion cells in temporal part of retina innervate ant. tectum

Axons from ganglion cells in nasal part of retina innervated post. tectum

Eph ligands, expressed in highest concentrations in post. tectum & lowest in ant. tectum

Similarly, ephrin receptors are in higher concentrations on temporal ganglion cells

Thus Temporal ganglion cells w/ highest number of receptors are repelled from highest concentration of Eph ligands of post. tectum. & thus frow to ant. tectum. (opposite is true for nasal ganglia & post. tectum)

Electrical activity is essental later in development, fine tuning the connections and providing the feedback or functional validation required for precise wiring of the nervous system

Limitations regarding synaptic specificity and chemical matching:

• A single directional gradient is not sufficient enough to enable neurons to reach target destinations. Other topographically graded distributions contribute

• Matching of axons to targets is not rigid, aeb removal of target tissue during development shows a shift in what neurons will iNN.

• Electrical activity is needed to fine tune connections, to provide fxn to the map

it's mediated by the muscle fibers themselves following the period of normal cell death in late embryonic development

It is the time period of plasticity in the young animal during which certain characteristics of vision can be altered by activity/inactivity. These changes are reversible if the alterations occur during this period, or irreversible if the attempt to change occur after this period has closed.

The effects of monocular deprivation on ocular dominance columns:

• Before the critical period - the working eye fails to retract its fibers and normal ocular column borders are not observed. This also leads to an absence of binocularly driven neurons.

• After the critical period, no deficits are seen.

A high number of fxnal neuronal cells on the ipsilateral side of the normal eye, a great reduction of fxnal neuronal cells on the contralateral side as well as a great reduction of binocularly driven neurons