Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix (
bHLH) transcription factor encoded by the ''Olig2'' gene. The protein is of 329 amino acids in length, 32 kDa in size and contains one basic helix-loop-helix DNA-binding domain. It is one of the three members of the bHLH family. The other two members are
OLIG1
Oligodendrocyte transcription factor 1 is a protein that in humans is encoded by the ''OLIG1'' gene.
See also
* Oligodendrocyte
* Transcription factor
* OLIG2
Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix ( bHLH) tr ...
and OLIG3. The expression of OLIG2 is mostly restricted in
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 ...
, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determining
motor neuron and
oligodendrocyte
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 ...
differentiation, as well as its role in sustaining replication in early development. It is mainly involved in diseases such as brain tumor and
Down syndrome
Down syndrome or Down's syndrome, also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21. It is usually associated with physical growth delays, mild to moderate intellectual dis ...
.
Function
OLIG2 is mostly expressed in restricted domains of the brain and
spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
ventricular zone which give rise to oligodendrocytes and specific types of neurons. In the spinal cord, the pMN region sequentially generates motor neurons and oligodendrocytes. During embryogenesis, OLIG2 first directs motor neuron fate by establishing a ventral domain of motor neuron progenitors and promoting neuronal differentiation. OLIG2 then switches to promoting the formation of oligodendrocyte precursors and oligodendrocyte differentiation at later stages of development. Apart from functioning as a neurogenic factor in specification and the differentiation of motor neurons and oligodendrocytes, OLIG2 also functions as an anti-neurogenic factor at early time points in pMN progenitors to sustain the cycling progenitor pool. This side of anti-neurogenicity of OLIG2 later plays a bigger role in malignancies like
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
...
.
The role of
phosphorylation has been highlighted recently to account for the multifaceted functions of OLIG2 in differentiation and proliferation. Studies showed that the phosphorylation state of OLIG2 at Ser30 determines the fate of cortical progenitor cells, in which cortical progenitor cells will either differentiate into astrocytes or remain as neuronal progenitors. Phosphorylation at a triple serine motif (Ser10, Ser13 and Ser14) on the other hand was shown to regulate the proliferative function of OLIG2. Another phosphorylation site Ser147 predicted by bioinformatics was found to regulate motor neuron development by regulating the binding between OLIG2 and NGN2. Further, OLIG2 contains a ST box composed of a string of 12 contiguous serine and threonine residues at position Ser77-Ser88. It is believed that phosphorylation at ST box is biologically functional, yet the role of it still remains to be elucidated in vivo.
OLIG2 has also been implicated in bovine horn ontogenesis. It was the only gene in the bovine ''polled'' locus to show differential expression between the putative horn bud and the frontal forehead skin.
Clinical Significance
OLIG2 in Cancer
OLIG2 is well recognized for its importance in cancer research, particularly in brain tumors and
leukemia
Leukemia ( also spelled leukaemia and pronounced ) is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or ...
. OLIG2 is universally expressed in
glioblastoma
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality ...
and other diffuse gliomas (
astrocytomas
Astrocytomas are a type of brain tumor. They originate in a particular kind of glial cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not us ...
,
oligodendrogliomas
Oligodendrogliomas are a type of glioma that are believed to originate from the oligodendrocytes of the brain or from a glial precursor cell. They occur primarily in adults (9.4% of all primary brain and central nervous system tumors) but are also ...
and
oligoastrocytomas
Oligoastrocytomas are a subset of brain tumors that present with an appearance of mixed glial cell origin, astrocytoma and oligodendroglioma. However, the term "Oligoastrocytoma" is now considered obsolete by the National Comprehensive Cancer Ne ...
), and is a useful positive diagnostic marker of these brain tumors. In particular, OLIG2 is selectively expressed in a subgroup of glioma cells that are highly tumorigenic, and is shown to be required for proliferation of human glioma cells implanted in the brain of
severe combined immunodeficiency
Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in diffe ...
(SCID) mice.
Though the molecular mechanism behind this tumorigenesis is not entirely clear, more studies have recently been published pinpointing diverse evidence and potential roles for OLIG2 in glioma progression. It is believed that OLIG2 promotes neural stem cell and progenitor cell proliferation by opposing
p53
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
pathway, which potentially contributes to glioma progression. OLIG2 has been shown to directly repress the p53 tumor-suppressor pathway effector p21
WAF1/CIP1, suppress p53
acetylation and impede the binding of p53 to several
enhancer sites. It is further found that the phosphorylation of triple-serine motif in OLIG2 is present in several glioma lines and is more tumorigenic than the unphosphorylated status. In a study using the U12-1 cell line for controlled expression of OLIG2, researchers showed that OLIG2 can suppress the proliferation of U12-1 by transactivating the ''p27
Kip1'' gene and can inhibit the motility of the cell by activating
RhoA
Transforming protein RhoA, also known as Ras homolog family member A (RhoA), is a small GTPase protein in the Rho family of GTPases that in humans is encoded by the ''RHOA'' gene. While the effects of RhoA activity are not all well known, it is ...
.
Besides glioma, OLIG2 is also involved in leukemogenesis. The ''Olig2'' gene was actually first identified in a study in T-cell
acute lymphoblastic leukemia, in which the expression of OLIG2 was found elevated after t(14;21)(q11.2;q22)
chromosomal translocation
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 ...
. The overexpression of OLIG2 was later shown present in malignancies beyond glioma and leukemia, such as breast cancer,
melanoma and
non-small cell lung carcinoma
Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to s ...
cell lines. It also has been shown that up-regulation of OLIG2 together with
LMO1
Rhombotin-1 is a protein that in humans is encoded by the ''LMO1'' gene.
LMO1 encodes a cysteine-rich, two LIM domain transcriptional regulator. It is mapped to an area of consistent chromosomal translocation in chromosome 11, disrupting it in T-c ...
and Notch1 helps to provide proliferation signals.
OLIG2 in Neural Diseases
OLIG2 is also associated with Down syndrome, as it locates at chromosome 21 within or near the Down syndrome critical region on the long arm. This region is believed to contribute to the cognitive defects of Down syndrome. The substantial increase in the number of forebrain inhibitory neurons often observed in Ts65dn mouse (a murine model of trisomy 21) could lead to imbalance between excitation and inhibition and behavioral abnormalities. However, genetic reduction of OLIG2 and OLIG1 from three copies to two rescued the overproduction of interneurons, indicating the pivotal role of OLIG2 expression level in Down syndrome. The association between OLIG2 and neural diseases (i.e.
schizophrenia
Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social wit ...
and
Alzheimer’s disease) are under scrutiny, as several
single nucleotide polymorphisms (SNPs) associated with these diseases in OLIG2 were identified by genome-wide association work.
OLIG2 also plays a functional role in neural repair. Studies showed that the number of OLIG2-expressing cells increased in the lesion after cortical stab-wound injury, supporting the role for OLIG2 in reactive
gliosis
Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, ...
. OLIG2 was also implicated in generating reactive
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 ...
possibly in a transient re-expression manner, but the mechanisms are unclear.
References
Further reading
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{{Transcription factors, g1
Transcription factors