Development of the Nervous System

Nervous system development has 4 stages:
1) specification of the neural cell identity (neural or glial),
2) neuron migration and axon outgrowth,
3) synapse formation with target (neurons, muscles or gland cells)
4) synaptic connection refinement (elimination of axon branches and cell death).

Specification of cell identity in the nervous system
Neurons in Drosophila arise from proneural clusters.
The neurogenic zone or neurectoderm consisting of cells that can become either neural cells or epidermis form on either side of the ventral mesoderm in the early embryo.
Proneural gene expression, such as the transcription factor genes of the achaete-scute complex gives the potential to become neural precursors.
This complex encodes a number of basic helix-loop-helix transcription factors that form homodimers and heterodimers that bind to genes that initiate neural specification.

Proneural clusters form within the neurectoderm .
Pair-rule genes, D/V genes and wingless (a segment polarity gene) pattern the proneural clusters.
One cell of a proneural cluster begins to express achaete at a high level to become the neuroblast which then leaves the ectoderm to move inside the neurula (and stops expressing achaete).
The achaete-scute complex also specifies the sensory nervous system and bristle formation.

Lateral inhibition allocates neuronal precursors.
One cell become the neural cell while lateral inhibition prevents surrounding cells from do so.
When Delta (the ligand) and Notch (the receptor) interact, activation of Notch leads to inhibition of the proneural genes and shutting down that program.
Initially all cells of the cluster express both Notch and Delta by one cell wins out (by expressing more Delta).

Development of Drosophila sensory organ and asymmetric cell divisions.
Most adult sensory organs (external sensory organs and internal chordotonal) arise from a single neuroblast.
Achaete-scute is required for external but not internal organs which requires the expression of the basic hlh factor atonal.
A sensory mother cells undergoes two cell divisions to generate a sensory bristle organ (a sensory neuron, a sheath cell and two support cells).
Numb is asymmetrically localized (before 1st division) and is required in the neuron & sheath precursor cell.

The Vertebrate nervous system
Most of the vertebrate CNS comes from the neural plate.
In addition sensory placoids in the head region give rise to the cranial nerves.
Specification of vertebrate neuronal precursors also involves lateral inhibition.
Delta activates Notch which inhibits synthesis of neurogenin (related to the achaete-scute proteins).
The one cell expressing neurogenin then expresses neuroD (a transcription factor required for neuronal differentiation).

The pattern of differentiation of cells along the D/V axis of the spinal cord depends on ventral and dorsal signals.
The spinal cord depends upon D/V patterning.
During early development, motor neuron are ventral, commissural neurons (along spinal cord) are dorsal.
Sensory neurons (from neural crest cells) arise laterally and dorsally.
Early on Pax gene expression differs along the D/V axis of the neural tube.
Sonic hh (from the floor plate of the neural tube) represses Pax3 & Pax7 to induce ventral cell fates.
Epidermal ectoderm sends dorsal signals (BMP4 & BMP7) to the closing neural tube which is propagated by expression BMP4 & dorsalin (TGF-beta family).
Expression of combinations of the LIM family of homeobox genes provide motor neurons with positional identities.
Neurons in the mammalian central nervous system arise from asymmetric cell divisions, then migrate away from the proliferative zone.
The neural tube generates a large number of different neuronal and glial cell types.

In both the brain and spinal cord, the neurons and glia arise from the ventricular proliferative zone (VPZ), a layer of epithelial cells lining the lumen of the neural tube.
Once formed the neuron does not divide again.
The mammalian cerebral cortex has 6 layers, each with distinctive cells.
All originate in the VPZ and migrate out to their final position along the elongated radial glial cells.
Each cortical neuron is specified before migration starts by the time when it is born (the time of its last mitotic division).
Early neurons migrate to close sites, while later ones travel past them to far locations.

Axonal Guidance

Neuronal survival, synapse formation and refinement
When axons reach their targets, they form synapses.
Junctions between nerve cells and muscle cells in vertebrates are neuromuscular junctions.
Neurons that do not connect with their target undergo apoptosis.
20,000 motor neurons are formed in the spinal cord of the chick but ~half die
Survival may depend upon establishing a functional synapse with a muscle cell.
Even after neuromuscular connections are made, some are eliminated until each muscle fiber is innervated by only one motor neuron.

Neurotrophic factors promote neuronal survival.
NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor),
NT-3 (neurotrophin-3) and NT-4/5 (neurotrophin-4/5) are neurotrophic factors that neuronal survival depends upon.
Trk proteins, receptor tyrosine kinases, are the neurotrophin receptors and act in the specificity of neuron type survival.

Interactions between nerve and muscle form the neuromuscular junction.
The axon branches end in large contacts with the endplate of the muscle fiber.
The neuromuscular junction (or synapse) is where the muscle and axon's plasma membranes are separated by the narrow synaptic cleft containing basal lamina (ECM) secreted by both cells.
The electrical impulse propagated down the axon is converted into a chemical signal which diffuse across the cleft to interact with receptors in the muscle cell to cause contraction.
Aggregation of acetylcholine receptors is aided by agrin activation of the Musk receptor and by neuregulin induction of localized acetylcholine receptor synthesis.