Gliogenesis
Encyclopedia
Gliogenesis is the generation of non-neuronal glia
populations derived from multipotent neural stem cells.
populations derived from multipotent neural stem 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 secrete myelin
for axon
insulation and 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.
, 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.
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.
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.
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.
s, are present to induce expression of proneural transcription factors like Neurogenin and Mash-1
. 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.
, of receptor proteins from the cell’s plasma membrane contributes to yet another mode of regulation of cellular function. While receptor internalization has the potential to regulate cellular functions in both a positive and negative fashion, internalization of the Notch receptor is shown to down-regulate the events leading to gliogenesis as this process is Notch-signaling dependent
During repression of gliogenesis, expression of the Notch-binding protein
, Numb, is elevated. Numb is suggested to function in two manners: 1) When expressed, Numb will interact with specific endocytic proteins and create a link between the notch receptor and the endocytic vesicles. The vesicle-receptor complex generated will be targeted back to the cell membrane and the membrane receptor will be recycled to the cell surface never reaching the nucleus. Alternatively, 2) Numb is suggested to recruit additional molecules other than endocytic proteins. In particular, ubiquitin ligases are shown to be recruited by Numb in mammals. The ubiquitin ligases ubiquitinates Notch and targets it for degradation Whatever the mechanism of Numb, the Notch receptor does not reach the nucleus and the transcription factors required for gliogenesis are not generated.
of neurodegenerative diseases and tumor
development within the nervous system. Recognizing the distinct pathways controlling neural stem fate, as discussed above, provides one the opportunity to intervene in the pathogenesis of these diseases.
of neurodegenerative diseases is associated with the disruption of gliogenic pathways and has been recently reviewed. The subventricular zone
(SVZ) of the forebrain is of special interest when evaluating errant gliogenic pathways as it is the largest store of neural stem cells in the brain. In Multiple Sclerosis
(MS) patients, lesions in this area are frequently observed and often extend outward toward the lateral ventricles
of the brain. Immune cells infiltrate the gliogenic regions within the SVZ adjacent to the lesions and initiate inflammatory response mechanisms in response to damage in this region. It is suggested that cytokine release during the inflammatory response reduces, foremost, the inherent neural stem cell populations, and jointly the potential of the remaining neural stem cell to differentiate to glial-fates. Consequently, a reduction of glial-derived oligodendroctyes, among others, compromise maintenance of myelin production for axon insulation, a hallmark phenotype among MS patients.
Consequences of gliogenesis disruption among other neurodegenerative diseases, such as Huntington’s, Parkinson’s, and Alzheimer’s Diseases are currently being investigated and strong mechanistic evidence is shown for pathogenesis similar to MS.
formation within the central nervous system. Loss of contact inhibition, cellular migration
, and unregulated proliferation are characteristic of gliomas. Consistent with other tissues, these malignant
phenotypes result most commonly from chromosome deletions, translocations, and point mutations. Linskey reviews both the genetic contributions and phenotypic observations of glioma
In non-carcinogenic neural stem cells, key regulatory mechanisms prevent uncontrolled gliogenic proliferation. However, such mechanisms are disrupted upon genetic damage. Studies now suggest glioma formation may result from cellular insensitivity to regulatory growth factors and cell signals, like neurogenin, that would normally inhibit further proliferation of glial cells. Conformational changes in receptor proteins are thought to occur, leaving the cell constitutively proliferating.
It can be expected that as the signaling pathways discussed are shown as prominent regulators during glial cell generation, these same pathways will become therapeutic targets for glial-derived and other CNS cancers. In medulloblastomas, in vivo
studies have begun targeting notch pathways by blocking Notch receptors with specific inhibitors preventing further differentiation. When used, pathway inhibitors provided 10-fold greater sensitivity to apoptotic induction in medulloblastoma cells Recognition of the regulatory mechanisms of gliogenesis provide new direction for intervention of neurogenic disorders.
In Regulation:
In Disease:
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
populations derived from multipotent neural stem cells.
Overview
Gliogenesis results in the formation of non-neuronal gliaGlial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
populations derived from multipotent neural stem cells. In this capacity, glial cells provide multiple functions to both the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) and the peripheral nervous system
Peripheral nervous system
The peripheral nervous system consists of the nerves and ganglia outside of the brain and spinal cord. The main function of the PNS is to connect the central nervous system to the limbs and organs. Unlike the CNS, the PNS is not protected by the bone of spine and skull, or by the blood–brain...
(PNS). Subsequent differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
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
Electrochemical gradient
An electrochemical gradient is a spatial variation of both electrical potential and chemical concentration across a membrane; that is, a combination of the membrane potential and the pH gradient...
and neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
transduction. Similarly derived, oligodendrocytes secrete myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
for axon
Axon
An axon is a long, slender projection of a nerve cell, or neuron, that conducts electrical impulses away from the neuron's cell body or soma....
insulation and electric signal transduction. Finally, microglial cells
Microglia
Microglia are a type of glial cell that are the resident macrophages of the brain and spinal cord, and thus act as the first and main form of active immune defense in the central nervous system . Microglia constitute 20% of the total glial cell population within the brain...
are derived from glial precursors and carry-out macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
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 cellsStem cell
This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
, an option is presented to proceed to enter neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
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
Invertebrate
An invertebrate is an animal without a backbone. The group includes 97% of all animal species – all animals except those in the chordate subphylum Vertebrata .Invertebrates form a paraphyletic group...
and vertebrate
Vertebrate
Vertebrates are animals that are members of the subphylum Vertebrata . Vertebrates are the largest group of chordates, with currently about 58,000 species described. Vertebrates include the jawless fishes, bony fishes, sharks and rays, amphibians, reptiles, mammals, and birds...
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 receptorsMembrane receptor
Cell surface receptors are specialized integral membrane proteins that take part in communication between the cell and the outside world...
that are ligand
Ligand
In coordination chemistry, a ligand is an ion or molecule that binds to a central metal atom to form a coordination complex. The bonding between metal and ligand generally involves formal donation of one or more of the ligand's electron pairs. The nature of metal-ligand bonding can range from...
activated. In the presence of ligand effectors, the intracellular domain of the receptor is cleaved and sequestered to the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
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
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
from arising. Both actions collectively function to promote glial fate.
In certain CNS tissue, JAK/STAT signaling
JAK-STAT signaling pathway
The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second...
is also known to promote gliogenesis Significant levels of the ciliary neurotrophic factor
Ciliary neurotrophic factor
Ciliary neurotrophic factor is a protein that in humans is encoded by the CNTF gene.CNTF has also been shown to be expressed by cells on the bone surface, and to reduce the activity of bone forming cells, osteoblasts.- Satiety effects :...
(CNTF) are expressed immediately preceding gliogensis in response to environmental cues allowing the activation of the JAK-STAT signaling pathway. Kinase
Kinase
In chemistry and biochemistry, a kinase is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates, a process referred to as phosphorylation. Kinases are part of the larger family of phosphotransferases...
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 DeltaYWHAZ
14-3-3 protein zeta/delta is a protein that in humans is encoded by the YWHAZ gene.-Interactions:YWHAZ has been shown to interact with TSC2, LIMK1, CDC25B, AKT1, BCAR1, Interleukin-9 receptor, C-Raf, HMGN1, Vimentin, Tau protein, Protein kinase Mζ, GP1BB, GP1BA, TNFAIP3, Bcl-2-associated death...
or Jagged
Jagged
Jagged is a 2006 album by Gary Numan, his first original album in over five years, following Pure in 2000. Stylistically Jagged was a development of its predecessor's chorus-driven, anthemic industrial sound, utilising heavier electronics and more prominent live drumming...
, 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 proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
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 in 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. BMPBMP
-In computing:* BMP file format, the file name extension for the Bitmap image file format.* Basic Multilingual Plane, related to the Unicode character set.* Beep Media Player, a multimedia player.-Biology:...
s, are present to induce expression of proneural transcription factors like Neurogenin and Mash-1
MASH-1
MASH-1 is a hash function based on modular arithmetic.- History :Despite many proposals, few hash functions based on modular arithmetic have withstood attack, and most that have tend to be relatively inefficient...
. 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.
Receptor Insensitivity
Recently, an alternative mechanism to regulate differentiation has been proposed in addition to inhibition through growth factors. Changes in local sensitivity of neural stem cells have been shown to modulate the differentiation capacity of growth factors. Over developmental time, neural stem cells lose the ability to respond to growth factors that influence differentiation as intrinsic changes occur to receptor structure and function of these cells. It has been shown Notch receptors require 50-fold higher concentrations of ligand effectors to initiate differentiation responses similar to that of developmentally earlier neural stem cells. Decrease in sensitivity of Notch receptors reduces the activity of Notch-signaling required for gliogenesis to occur. Consequently, neural stem cells have developed a general mechanism limiting further differentiation after intense specialization during the early developmental periods.Receptor Internalization
The internalization, or endocytosisEndocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, of receptor proteins from the cell’s plasma membrane contributes to yet another mode of regulation of cellular function. While receptor internalization has the potential to regulate cellular functions in both a positive and negative fashion, internalization of the Notch receptor is shown to down-regulate the events leading to gliogenesis as this process is Notch-signaling dependent
During repression of gliogenesis, expression of the Notch-binding protein
NUMB (gene)
Protein numb homolog is a protein that in humans is encoded by the NUMB gene.-Interactions:NUMB has been shown to interact with Adaptor-related protein complex 2, alpha 1, Mdm2, L1, DPYSL2, SIAH1, P53 and LNX1.-Further reading:...
, Numb, is elevated. Numb is suggested to function in two manners: 1) When expressed, Numb will interact with specific endocytic proteins and create a link between the notch receptor and the endocytic vesicles. The vesicle-receptor complex generated will be targeted back to the cell membrane and the membrane receptor will be recycled to the cell surface never reaching the nucleus. Alternatively, 2) Numb is suggested to recruit additional molecules other than endocytic proteins. In particular, ubiquitin ligases are shown to be recruited by Numb in mammals. The ubiquitin ligases ubiquitinates Notch and targets it for degradation Whatever the mechanism of Numb, the Notch receptor does not reach the nucleus and the transcription factors required for gliogenesis are not generated.
Gliogenic-Associated Pathology
Recent work has demonstrated abnormalities in the signaling pathways responsible for gliogenesis and neurogenesis could contribute to the pathogenesisPathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
of neurodegenerative diseases and tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
development within the nervous system. Recognizing the distinct pathways controlling neural stem fate, as discussed above, provides one the opportunity to intervene in the pathogenesis of these diseases.
Gliogenesis and Neurodegenerative Disease
The pathologyPathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
of neurodegenerative diseases is associated with the disruption of gliogenic pathways and has been recently reviewed. The subventricular zone
Subventricular zone
The subventricular zone is a paired brain structure situated throughout the lateral walls of the lateral ventricles. It has been associated with having four distinct layers of variable thickness and cell density, as well as cellular composition....
(SVZ) of the forebrain is of special interest when evaluating errant gliogenic pathways as it is the largest store of neural stem cells in the brain. In Multiple Sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
(MS) patients, lesions in this area are frequently observed and often extend outward toward the lateral ventricles
Lateral ventricles
The lateral ventricles are part of the ventricular system of the brain. Classified as part of the telencephalon, they are the largest of the ventricles....
of the brain. Immune cells infiltrate the gliogenic regions within the SVZ adjacent to the lesions and initiate inflammatory response mechanisms in response to damage in this region. It is suggested that cytokine release during the inflammatory response reduces, foremost, the inherent neural stem cell populations, and jointly the potential of the remaining neural stem cell to differentiate to glial-fates. Consequently, a reduction of glial-derived oligodendroctyes, among others, compromise maintenance of myelin production for axon insulation, a hallmark phenotype among MS patients.
Consequences of gliogenesis disruption among other neurodegenerative diseases, such as Huntington’s, Parkinson’s, and Alzheimer’s Diseases are currently being investigated and strong mechanistic evidence is shown for pathogenesis similar to MS.
Gliogenesis and Glial Tumors
Disruption of controlled glial generation subsequently results in tumorigenesis and gliomaGlioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
formation within the central nervous system. Loss of contact inhibition, cellular migration
Cellular migration
Cellular migration is the movement of cells in the body to their proper position.-Purpose:During the Prenatal development, the basic structures for all organs in the body are created...
, and unregulated proliferation are characteristic of gliomas. Consistent with other tissues, these malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
phenotypes result most commonly from chromosome deletions, translocations, and point mutations. Linskey reviews both the genetic contributions and phenotypic observations of glioma
In non-carcinogenic neural stem cells, key regulatory mechanisms prevent uncontrolled gliogenic proliferation. However, such mechanisms are disrupted upon genetic damage. Studies now suggest glioma formation may result from cellular insensitivity to regulatory growth factors and cell signals, like neurogenin, that would normally inhibit further proliferation of glial cells. Conformational changes in receptor proteins are thought to occur, leaving the cell constitutively proliferating.
Therapeutic Intervention of Gliogenic-Derived Pathogenesis
Understanding the pathology of these neurodegenerative diseases and establishment of therapeutic interventions require recognition of the processes of induction and inhibition of gliogenesis and the regulating mechanisms coordinating the intricate system established from both actions. Cell replacement strategies are now intensely studied as a possible therapeutic intervention of glial associated neurodegenerative disorders and glial tumors. Similar to any novel strategy, however, set-backs and liabilities accompany the promises this technique withholds. For cell replacement to function efficiently and demonstrate robust results, introduced cells must be 1) generated in sufficient yield and 2) immunocompatible with the host and 3) able to sustain self-growth. New perspectives within stem cell biology and gliogenesis regulation have provided new insights within the past decade to begin addressing these challenges. Reprogramming terminally differentiated neural lineages back to neural stem cells permits regeneration of a multipotent self-lineage that can be redirected to cellular-fates affected during neurogenerative diseases, oligodendrocytes with MS patients or astrocytes in those affected with Alzheimer’s, in the presence of proper environmental signals.It can be expected that as the signaling pathways discussed are shown as prominent regulators during glial cell generation, these same pathways will become therapeutic targets for glial-derived and other CNS cancers. In medulloblastomas, in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
studies have begun targeting notch pathways by blocking Notch receptors with specific inhibitors preventing further differentiation. When used, pathway inhibitors provided 10-fold greater sensitivity to apoptotic induction in medulloblastoma cells Recognition of the regulatory mechanisms of gliogenesis provide new direction for intervention of neurogenic disorders.
Further reading
Gliogenesis Induction:- Gaiano N, Fishell G. (2002). The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci. 25: 471-90. PMID 12052917
In Regulation:
- Morrsion SJ. (2000) The last shall not be the first: the ordered generation of progeny from stem cells. Neuron 28: 1-3. PMID: 11086973.
- Morrison, SJ. (2001) Neuronal potential and lineage determination by neural stem cells. Curr Opin Cell Biol. 13;6: 666-72 PMID: 11698181.
In Disease:
- Multiple Sclerosis: Pluchino S, Zanotti L and Martino G. (2007) Rationale for the use of neural stem/precursor cells in immunemediated demyelinating disorders. J Neurol. 254: I23–I28.