Gliogenesis is the generation of non-neuronal glia populations derived from multipotent neural stem cells.
Overview Gliogenesis results in the formation of non-neuronal glia populations from neuronal cells. In this capacity, glial cells provide multiple functions to both the central nervous system (CNS) and the peripheral nervous system (PNS). Subsequent differentiation of glial cell populations results in function-specialized glial lineages. Glial cell-derived astrocytes are specialized lineages responsible for modulating the chemical environment by altering ion gradients and neurotransmitter transduction. Similarly derived, oligodendrocytes produce myelin, which insulates axons to facilitate electric signal transduction. Finally, microglial cells are derived from glial precursors and carry out macrophage-like properties to remove cellular and foreign debris within the central nervous system ref. Functions of glial-derived cell lineages are reviewed by Baumann and Hauw. Gliogenesis itself, and differentiation of glial-derived lineages are activated upon stimulation of specific signaling cascades. Similarly, inhibition of these pathways is controlled by distinct signaling cascades that control proliferation and differentiation. Thus, elaborate intracellular-mechanisms based on environmental signals are present to regulate the formation of these cells. As regulation is much more known in the CNS, its mechanisms and components will be focused on here. Understanding the mechanisms in which gliogenesis is regulated provides the potential to harness the ability to control the fate of glial cells and, consequently, the ability to reverse neurodegenerative diseases.
Gliogenesis induction Following the generation of neural stem cells, an option is presented to proceed to enter neurogenesis and form new neurons within the CNS, shift into gliogenesis, or remain in a pluripotent cell state. The mechanisms determining the ultimate fate of neural stem cells are conserved among both invertebrate and vertebrate species and are determined from extracellular cues generated from neighboring cells. Most work to derive such mechanisms, however, began with invertebrate models. Conclusions reached from these studies have directed attention to specific signaling molecules and effector pathways that are responsible for mediating the cellular events required for maintaining or changing the neural stem cell fate.
Signaling effectors
Notch signaling is known to mediate prominent cellular events that result in gliogenesis. The Notch family proteins are transmembrane receptors that are ligand activated. In the presence of ligand effectors, the intracellular domain of the receptor is cleaved and sequestered to the nucleus where it acts to influence expression of transcription factors required for gliogenesis. Transcription factors synthesized as a result of the Notch signaling cascade bind to promoters of genes responsible for glial determination. Additionally, Notch signaling also acts to downregulate many genes responsible for neuronal development, thus inhibiting a neuron phenotype from arising. Both actions collectively function to promote glial fate. In certain CNS tissue, JAK/STAT signaling is also known to promote gliogenesis Significant levels of the ciliary neurotrophic factor (CNTF) are expressed immediately preceding gliogensis in response to environmental cues allowing the activation of the JAK-STAT signaling pathway. Kinase activity phosphorylates STAT proteins which then are recruited by transcription factors. The STAT complex is targeted to promoters of genes responsible for gliogenesis activation. It is important to recognize that when isolated, receptor-mediated signaling cascades can produce distinct actions, however, when in vivo coopertivity often exists among receptor pathways and results in much more complicated cellular actions.
Signaling molecules The receptor-proteins responsible for gliogenic pathways are often ligand activated. Upon binding of Delta or Jagged, the notch-mediated signaling cascades are activated leading to gliogenic transcription factor production as discussed above. As noted for receptor-proteins, in vivo interactions among different growth factor responsible for gliogenesis and other cell fates produce very different roles than when isolated.
Gliogenesis regulation To ensure proper temporal differentiation as well as correct quantities of glial cell formation, gliogenesis is subjected to stringent regulatory mechanisms. Proneural factors are expressed in high concentrations during times in which glial cells are not to form or neuron development is needed. These protein signals function to inhibit many of the signals utilized during the induction of gliogenesis. Additionally, the properties and abundance of receptor molecules that mediate gliogenesis are altered, consequently disrupting propagation of induction signals.
Signaling inhibition During periods in which glial cell formation is discouraged, neural stem cells have the option to remain pluripotent or switch pathway lineages and begin forming neurons during neurogenesis. If neuron development is instructed, neurogenic factors, i.e. BMPs, are present to induce expression of proneural transcription factors like Neurogenin and ASCL1. These transcription factors function to interact with transcription factors generated from Notch signaling. Consequently, this complex is sequestered away from promoters activating gliogenesis and now directed to promoters that influence activity directed for neuron development. Neurogenin proteins regulate JAK/STAT signaling by similar mechanisms.
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