Gliogenesis is the generation of non-neuronal

glia Glia, also called glial cells (gliocytes) or neuroglia, are non-neuronal cells in the central nervous system (brain and spinal cord) and the peripheral nervous system that do not produce electrical impulses. They maintain homeostasis, form myel ...

populations derived from

multipotent Pluripotency: These are the cells that can generate into any of the three Germ layers which imply Endodermal, Mesodermal, and Ectodermal cells except tissues like the placenta. According to Latin terms, Pluripotentia means the ability for many thin ...

neural stem cell Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...

Overview

Gliogenesis results in the formation of non-neuronal

populations from neuronal cells. In this capacity, glial cells provide multiple functions to both the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

(CNS) and the

peripheral nervous system The peripheral nervous system (PNS) is one of two components that make up the nervous system of bilateral animals, with the other part being the central nervous system (CNS). The PNS consists of nerves and ganglia, which lie outside the brain ...

(PNS). Subsequent differentiation of glial cell populations results in function-specialized glial lineages. Glial cell-derived

astrocytes Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of endo ...

are specialized lineages responsible for modulating the chemical environment by altering ion gradients and neurotransmitter transduction. Similarly derived,

oligodendrocytes Oligodendrocytes (), or oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons in the central nervous system of jawed vertebrates, equivalent to the function performed by Schwann cells in the ...

produce

myelin Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be ...

, which insulates

axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...

s to facilitate electric signal transduction. Finally,

microglial cells Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune ...

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 Neural stem cells (NSCs) are self-renewing, multipotent cells that firstly generate the radial glial progenitor cells that generate the neurons and glia of the nervous system of all animals during embryonic development. Some neural progenitor ste ...

, 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 Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...

and

vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...

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 In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...

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 Cell surface receptors (membrane receptors, transmembrane receptors) are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving (binding to) extracellular molecules. They are specialized integral m ...

that are

ligand In coordination chemistry, a ligand is an ion or molecule ( functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elec ...

activated. In the presence of ligand effectors, the intracellular domain of the receptor is cleaved and sequestered to the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom * Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucl ...

where it acts to influence expression of

transcription factors In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fun ...

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 A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological pr ...

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 Ciliary neurotrophic factor is a protein that in humans is encoded by the ''CNTF'' gene. The protein encoded by this gene is a polypeptide hormone and neurotrophic factor whose actions have mainly been studied in the nervous system where it p ...

(CNTF) are expressed immediately preceding gliogensis in response to environmental cues allowing the activation of the JAK-STAT signaling pathway. Kinase activity

phosphorylates In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, whi ...

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 Delta commonly refers to: * Delta (letter) (Δ or δ), a letter of the Greek alphabet * River delta, at a river mouth * D ( NATO phonetic alphabet: "Delta") * Delta Air Lines, US * Delta variant of SARS-CoV-2 that causes COVID-19 Delta may also ...

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 Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

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

Neuro-Gliogenesis via Lateral 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 Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. It is one of many gene families related to the ''atonal'' gene in Drosophila. Other positive regulators of neuronal differentiation also exp ...

and

ASCL1 Achaete-scute homolog 1 is a protein that in humans is encoded by the ''ASCL1'' gene. Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scu ...

. 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 A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for reg ...

. 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 endocytosis, 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 A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquiti ...

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

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

of neurodegenerative diseases and

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

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

pathology Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...

of neurodegenerative diseases is associated with the disruption of gliogenic pathways and has been recently reviewed. The

subventricular zone The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zone ...

(SVZ) of the

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hindbrain (rhombencephalon) are the three primary ...

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 The lateral ventricles are the two largest ventricles of the brain and contain cerebrospinal fluid (CSF). Each cerebral hemisphere contains a lateral ventricle, known as the left or right ventricle, respectively. Each lateral ventricle resemble ...

of the brain.

Immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...

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 Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecu ...

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 oligodendrocytes, 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 Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

, 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

glioma A glioma is a type of tumor that starts in the glial cells of the brain or the spine. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours. Signs and symptoms ...

formation within the central nervous system. Loss of contact inhibition,

cellular migration Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular direct ...

, and unregulated proliferation are characteristic of gliomas. Consistent with other tissues, these

malignant Malignancy () is the tendency of a medical condition to become progressively worse. Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...

phenotypes result most commonly from chromosome deletions,

translocations In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translo ...

, and

point mutations A point mutation is a genetic mutation where a single nucleotide base is changed, inserted or deleted from a DNA or RNA sequence of an organism's genome. Point mutations have a variety of effects on the downstream protein product—consequence ...

. 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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

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 Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes incl ...

induction in medulloblastoma cells Hallahan AR, Pritchard JI, Hansen S, et al. (2004) The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res. 64: 7794-7800. Recognition of the regulatory mechanisms of gliogenesis provide new direction for intervention of neurogenic disorders.