The study of neural development draws on both neuroscience and developmental biology to describe the cellular and molecular mechanisms by which complex nervous systems emerge during embryonic development and throughout life.

Some landmarks of embryonic neural development include the birth and differentiation of neurons from stem cell precursors, the migration of immature neurons from their birthplaces in the embryo to their final positions, outgrowth of axons from neurons and guidance of the motile growth cone through the embryo towards postsynaptic partners, the generation of synapses between these axons and their postsynaptic partners, and finally the lifelong changes in synapses which are thought to underlie learning and memory.

Typically, these neurodevelopmental processes can be broadly divided into two classes: activity-independent mechanisms and activity-dependent mechanisms. Activity-independent mechanisms are generally believed to occur as hardwired processes determined by genetic programs played out within individual neurons. These include differentiation, migration and axon guidance to their initial target areas. These processes are thought of as being independent of neural activity and sensory experience. Once axons reach their target areas, activity-dependent mechanisms come into play. Neural activity and sensory experience will mediate formation of new synapses, as well as synaptic plasticity, which will be responsible for refinement of the nascent neural circuits.

Developmental neuroscience uses a variety of animal models including mice Mus musculus , the fruit fly Drosophila melanogaster , the zebrafish Danio rerio, Xenopus laevis tadpoles and the worm Caenorhabditis elegans, among others.

Formation of the spinal cord

Neurulation

See embryogenesis for understanding the animal development up to this stage.

Neurulation is the formation of the neural tube from the ectoderm of the embryo. It follows gastrulation in all vertebrates. During gastrulation cells migrate to the interior of embryo, forming three germ layers— the endoderm (the deepest layer), mesoderm and ectoderm (the surface layer)—from which all tissues and organs will arise. In a simplified way, it can be said that the ectoderm gives rise to skin and nervous system, the endoderm to the guts and the mesoderm to the rest of the organs.

After gastrulation the notochord—a flexible, rod-shaped body that runs along the back of the embryo—has been formed from the mesoderm. The notochord sends signals to the overlying ectoderm, inducing it to become neuroectoderm. This results in a strip of neuronal stem cells that runs along the back of the fetus. This strip is called the neural plate, and is the origin of the entire nervous system.

The neural plate folds outwards during the third week of gestation to form the neural groove. Beginning in the future neck region, the neural folds of this groove close to create the neural tube. The anterior (front) part of the neural tube is called the basal plate; the posterior (rear) part is called the alar plate. The hollow interior is called the neural canal. By the end of the fourth week of gestation, the open ends of the neural tube (the neuropores) close off.

Formation of brain parts

Late in the fourth week, the superior part of the neural tube flexes at the level of the future midbrain—the mesencephalon. Above the mesencephalon is the prosencephalon (future forebrain) and beneath it is the rhombencephalon (future hindbrain).

The optical vesicle (which will eventually become the optic nerve, retina and iris) forms at the basal plate of the prosencephalon. The alar plate of the prosencephalon expands to form the cerebral hemispheres (the telencephalon) whilst its basal plate becomes the diencephalon. Finally, the optic vesicle grows to form an optic outgrowth.

Patterning of the nervous system

In chordates, dorsal ectoderm forms all neural tissue and the nervous system. Patterning occurs due to specific environmental conditions - different concentrations of signaling molecules

Dorsalventral axis

The ventral half of the neural plate is controlled by the notochord, which acts as the 'organiser'. The dorsal half is controlled by the ectoderm plate which flanks the neural plate on either side.

Ectoderm follows a default pathway to become neural tissue. Evidence for this comes from single, cultured cells of ectoderm which go on to form neural tissue. This is postulated to be because of a lack of BMPs, which are blocked by the organiser. The organiser may produce molecules such as follistatin, noggin and chordin which inhibit BMPs.

The ventral neural tube is patterned by Shh from the notochord, which acts as the inducing tissue. The Shh inducer causes differentiation of the floor plate. Shh-null tissue fails to generate all cell types in the ventral tube, suggesting Shh is necessary for its induction. The hypothesised mechanism suggests that Shh binds patched, relieving patched inhibition of smoothend, leading to activation of gli transcription factors.

In this context Shh acts as a morphogen - it induces cell differentiation dependent on its concentration. At low concentrations it forms ventral interneurones, at higher concentrations it induced motor neurone development, and at highest concentrations it induces floor plate differentiation. Failure of Shh-modulated differentiation causes haloprosencephaly.

The dorsal neural tube is patterned by BMPS from the epidermal ectoderm flanking the neural plate. These induce sensory interneurones by activating Sr/Thr kinases and altering SMAD transcription factor levels.

Rostrocaudal axis

Dorsoventral induction of ventral tissue expresses characteristic forebran tissue. Other signals manipulate posterior tissues differentiation, including FGF and retinoic acid.

The hindbrain, for example, is patterned by Hox genes, which are expressed in overlapping domains along the anteroposterior axis. The 5' genes in this cluster and expressed most posteriorly. Hoxb-1 is expressed in rhombomere 4 and gives rise to the facial nerve. Without this Hoxb-1 expression, a nerve which is similar to the trigeminal nerve arises.

Neuronal migration

Neuronal migration is the method by which neurons travel from their origin or birth place to their final position in the brain. There are several ways they can do this, e.g. by radial migration or tangential migration. (see time lapse sequences of radial migration (also known as glial guidance) and somal translocation.)

Radial migration

Neuronal precursor cells proliferate in the ventricular zone of the developing neocortex. The first postmitotic cells to migrate form the preplate which are destined to become Cajal-Retzius cells and subplate neurons. These cells do so by somal translocation. Neurons migrating with this mode of locomotion are bipolar and attachs the leading edge of the process to the pia. The soma is then transported to the pial surface by nucleokinesis, a process by which a microtubule "cage" around the nucleus elongates and contracts in association with the centrosome to guide the nucleus to its final destination. Radial glia, whose fibers serve as a scaffolding for migrating cells, can itself divide or translocate to the cortical plate and differentiate either into astrocytes or neurons. Somal translocation can occur at any time during development.

Subsequent waves of neurons split the preplate by migrating along radial glial fibres to form the cortical plate. Each wave of migrating cells travel past their predecessors forming layers in an inside-out manner, meaning that the youngest neurons are the closest to the surface. It is estimated that glial guided migration represents 90% of migrating neurons in human and about 75% in rodents.

Tangential migration

Most interneurons migrate tangentially through multiple modes of migration to reach their appropriate location in the cortex. An example of tangential migration is the movement of Cajal-Retzius cells from the ganglionic eminence to the cerebral cortex. One example of ongoing tangential migration in a mature organism, observed in some animals, is the rostral migratory stream connecting subventricular zone and olfactory bulb.

Others

There is also a method of neuronal migration called multipolar migration. This is seen in multipolar cells, which are abundantly present in the cortical intermediate zone. They do not resemble the cells migrating by locomotion or somal translocation. Instead these multipolar cells express neuronal markers and extend multiple thin processes in various directions independently of the radial glial fibers.

Support and selection of neurons

Survival of a neuron depends on competitions between synapses. The processing ability of a synapse is refined through its use, called selection via correlated activity. Evidence for this comes from the neuromuscular junction.

Neuromuscular junction

Clustering of muscarinic receptors at synapses is dependent on agrin, which is released from the neurone when it is stimulated. This shows how neurones can strengthen a synapse by inducing an upregulation of receptors for its neurotransmission through activity alone. In this instance, agrin transuces the signal via MuSK receptor to rapsyn. MuSK receptor-null tissue shows no muscarinic receptor clustering at the synapse. Increased expression of the muscarinic receptor is also caused by neuregulin. Heterozygous mice for the neuregulin genes show decreased muscarinic receptor expression by 50%.

Denervation sensitivity shows how nerve activity causes a deregulation of muscarinic receptors at non-synpatic sites. When the nerve is cut, receptors become upregulated in areas other than the synpase. Acetylcholine is thought to cause this effect via influx of calcium.

Synapse Elimination

Several motorneurones compete for each neuromuscular junction, but only one survives till adulthood. The evolutionary purpose for this has been suggested to be a method that ensures each muscle fibre is innervated. Competition in vitro has been shown to involve a limited neurotrophic substance that is released, or that neural activity infers advantage to strong post-synaptic connections by giving resistance to a toxin also released upon nerve stimulation. In vivo it is suggested that muscle fibres select the strongest neurone through a retrograde signal.

Neural development in the adult nervous system

Neural development in the adult nervous system includes mechanisms such as remyelination, generation of new neurons, glia, axons, myelin or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms and especially, the extent and speed.

See also

• Axon guidance
• Pioneer neuron
• Neural Darwinism
• Neurodevelopmental disorder
• Pre- and perinatal psychology
• Brain development timelines

References

External links

• Myers, P.Z., 2004. "Neurulation in Zebrafish" in Pharyngula
• Neural Development (peer-reviewed open access journal).