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Neurogenesis

From Wikipedia, the free encyclopedia

Neurogenesis is the process by which nervous system cells, including neurons and glia, are produced by neural stem cells. Neural stem cells are cells that have the potential to produce many different types of nervous system cells. They include neuroepithelial (NEP) stem cells, radial glial cells (RGCs), basal progenitors (BPs), subventricular zone astrocytes, and subgranular zone radial astrocytes, among others. Neurogenesis is most abundant during embryonic development, when an animal embryo is forming and growing, but it continues throughout adult life.

Neurogenesis begins during embryogenesis in all animals and is responsible for producing all the neurons of the organism. Prior to the period of neurogenesis, neural stem cells first multiply. Neurons are derived from the ectoderm, a layer of the developing embryo which also goes on to form the organism's skin. During development, the parts of the ectoderm destined to become neurons start to multiply and then differentiate, forming the many types of neurons found in the adult nervous system. The multiplying neural progenitors form a groove, called the neural groove, which then seals and becomes the neural tube, which is where most embryonic neurogenesis takes place.

The primary neural stem cell of the mammalian brain, called a radial glial cell, resides in an embryonic zone called the ventricular zone, which lies adjacent to the developing brain ventricles on the inside of the neural tube. After the neural progenitor cells have sufficiently proliferated, they start to differentiate based on genetic and chemical signals. The process of neurogenesis then involves a final cell division of the parent neural stem cell, which produces daughter neurons that will never divide again. Most neurons of the human central nervous system live the lifetime of the individual. The molecular and genetic factors influencing neurogenesis notably include the Notch pathway, and many genes have been linked to Notch pathway regulation. 

Invertebrate Neurogenesis

In Drosophila (fruit flies), the precursors of both the PNS and CNS emerge from domains of ectodermal cells termed proneural clusters. These cells have both epidermal and neuronal potential. Only one or a few cells in each cluster are singled out to become neuronal precursors whereas the remaining cells adopt the epidermal fate. The lateral inhibition, of the remaining cells by the enlarging neuroblasts ensures that only one neuroblast arises from the proneural cluster. All cells of the cluster retain their neuroblast forming potential during enlargement of the neuroblast, but lose this potential by the time the cell is about to divide. Proneural activity results in the selection of progenitors that are committed to a neural fate but remain multipotent, with sense organ progenitors giving rise to neurons, glia and other non-neuronal cell types. Additionally, some neuroblasts of the central nervous system also generate both neurons and glia. Progenitors of the peripheral and central nervous system only begin to divide after proneural gene expression has subsided. The way in which neural progenitors are specified and spatially arranged gives the immature embryonic CNS a certain shape and inner architecture, which in turn foreshadows the structure of the mature CNS.

Regulatory Genes in Invertebrate Neurogenesis

In Drosophila and various vertebrates, proneural clusters form a highly invariant pattern within the neuroectoderm. Proneural genes move cells out of the progenitor state and trigger neural differentiation. In the central nervous system (CNS), neuroblasts divide to produce another neuroblast and a ganglion mother cell (GMC), which will divide once more to generate two neurons or glia. The process of neuroblast formation depends on the functions of the proneural genes. One example of neurogenesis regulators in invertebrates, are the proneural genes that are members of the achaete-scute complex (AS-C). The formation of neuroblasts depends on the Achaete-scute complex genes – achaete (ac), scute (sc), lethal of scute (lsc), asense (ase). When ectopically expressed, the four AS-C genes induce the development of ectopic external sense organs at the expense of epidermis. Another regulator of neurogenesis in invertebrates is the prospero gene. Prospero (pros) encodes an evolutionarily conserved atypical homeodomain protein (pros) that is expressed in all neuronal lineages. This gene has shown to aid in the specification of ganglion mother cells in the central nervous system.

Genetic Findings in Drosophila

(Although present in Drosophila, some of these findings are also applicable to vertebrates- for example the function of the Notch signalling pathway)

The Notch signaling pathway acts locally within the proneural clusters to control the spatial and temporal pattern at which neurons/neural progenitors are born. Proneural genes trigger an inhibitory feedback loop (‘‘lateral inhibition’’) within the proneural clusters by transcriptionally activating Notch ligands. Cells receiving high levels of Notch activity turn down proneural genes and express another class of basic helix-loop-helix (bHLH) genes which inhibit neural differentiation. Cells with low levels of Notch activity progress toward a stage of commitment as neural progenitor or neural precursor. Conserved factors, such as Prospero in Drosophila, trigger the exit from the cell cycle and initiate neural differentiation. One developmental mechanism to achieve high precision in neuronal differentiation and architecture is by fixed neural lineages. Intrinsic determinants are expressed in progenitors that divide according to an asymmetric, fixed pattern and are then channeled into specific daughter cells. Depending on which determinant the cell inherits, a daughter cell adopts a specific cell type.

Adult Neurogenesis

The process of neurogenesis is also being researched in adult organisms. In mammals, adult neurogenesis has been shown to occur in two primary regions in the brain: the dentate gyrus of the hippocampus and the subventricular zone (SVZ). In some mammals, such as rodents, the olfactory bulb is a zone which features integration of adult-born neurons, which migrate from the SVZ through the rostral migratory stream (RMS). In some vertebrates, regenerative neurogenesis has also been shown to occur. Many environmental factors, such as exercise, stress, and antidepressants, have been shown to change the rate of neurogenesis within the hippocampus. For more information, see adult neurogenesis.

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