Oligodendrocyte transcription factor (OLIG2) is a basic helix-loop-helix (bHLH) transcription factor encoded by theOLIG2 gene. The protein is of 329 amino acids in length, 32 kDa in size and contains one basic helix-loop-helix DNA-binding domain.[5] It is one of the three members of the bHLH family. The other two members areOLIG1 and OLIG3. The expression of OLIG2 is mostly restricted incentral nervous system, where it acts as both an anti-neurigenic and a neurigenic factor at different stages of development. OLIG2 is well known for determiningmotor neuron andoligodendrocyte differentiation, as well as its role in sustaining replication in early development. It is mainly involved in diseases such as brain tumor andDown syndrome.
OLIG2 is mostly expressed in restricted domains of the brain andspinal cordventricular zone which give rise to oligodendrocytes and specific types of neurons. In the spinal cord, the pMN region sequentially generates motor neurons and oligodendrocytes. Duringembryogenesis, 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 likeglioma.[6]
The role ofphosphorylation 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.[7] Phosphorylation at a triple serine motif (Ser10, Ser13 and Ser14) on the other hand was shown to regulate the proliferative function of OLIG2.[8] Another phosphorylation site Ser147 predicted by bioinformatics was found to regulate motor neuron development by regulating the binding between OLIG2 andNGN2.[9] 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,[10] yet the role of it still remains to be elucidated in vivo.[11]
OLIG2 has also been implicated in bovine horn ontogenesis. It was the only gene in the bovinepolled locus to show differential expression between the putative horn bud and the frontal forehead skin.[12]
OLIG2 is well recognized for its importance in cancer research, particularly in brain tumors andleukemia. OLIG2 is universally expressed inglioblastoma and other diffuse gliomas (astrocytomas,oligodendrogliomas andoligoastrocytomas), and is a useful positive diagnostic marker of these brain tumors.[13] Although in normal brain tissue OLIG2 expresses mostly on oligodendrocytes but not on mature astrocytes, in adultglioma, OLIG2 expresses on bothIDH1 orIDH2-mutant adult lower gradeastrocytoma andoligodendroglioma on similar levels, but it is expressed on a lower level on IDH-wildtypeglioblastoma.[14] OLIG2 overexpression is a good surrogate marker for IDH mutation with anAUC of 0.90, but predicts poorly (AUC = 0.55) for 1p/19q co-deletion, a class-defining chromosomal alteration foroligodendroglioma.[14] In survival analysis, highermRNA levels of OLIG2 were associated with better overall survival, but this association was completely dependent on IDH mutation status.[14]
In particular, OLIG2 is selectively expressed in a subgroup of glioma cells that are highly tumorigenic,[15] and is shown to be required for proliferation of human glioma cells implanted in the brain ofsevere combined immunodeficiency (SCID) mice.[16]
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 opposingp53 pathway, which potentially contributes to glioma progression. OLIG2 has been shown to directly repress the p53 tumor-suppressor pathway effectorp21WAF1/CIP1,[17] suppress p53acetylation and impede the binding of p53 to severalenhancer sites.[18] 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.[19] 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 thep27Kip1 gene[20] and can inhibit the motility of the cell by activatingRhoA.[21]
Besides glioma, OLIG2 is also involved in leukemogenesis. TheOlig2 gene was actually first identified in a study in T-cellacute lymphoblastic leukemia, in which the expression of OLIG2 was found elevated after t(14;21)(q11.2;q22)chromosomal translocation.[22] The overexpression of OLIG2 was later shown present in malignancies beyond glioma and leukemia, such as breast cancer,melanoma andnon-small cell lung carcinoma cell lines.[23] It also has been shown that up-regulation of OLIG2 together withLMO1 and Notch1 helps to provide proliferation signals.
OLIG2 is also associated withDown syndrome, as it locates atchromosome 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 offorebrain inhibitory neurons often observed inTs65dn mouse (amurine 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.[24] The association between OLIG2 and neural diseases (i.e.schizophrenia andAlzheimer's disease) are under scrutiny, as severalsingle nucleotide polymorphisms (SNPs) associated with these diseases in OLIG2 were identified bygenome-wide association work.[25][26]
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 reactivegliosis.[27] OLIG2 was also implicated in generating reactiveastrocytes possibly in a transient re-expression manner, but the mechanisms are unclear.[28]
^Allais-Bonnet A, Grohs C, Medugorac I, Krebs S, Djari A, Graf A, Fritz S, Seichter D, Baur A, Russ I, Bouet S, Rothammer S, Wahlberg P, Esquerré D, Hoze C, Boussaha M, Weiss B, Thépot D, Fouilloux MN, Rossignol MN, van Marle-Köster E, Hreiðarsdóttir GE, Barbey S, Dozias D, Cobo E, Reversé P, Catros O, Marchand JL, Soulas P, Roy P, Marquant-Leguienne B, Le Bourhis D, Clément L, Salas-Cortes L, Venot E, Pannetier M, Phocas F, Klopp C, Rocha D, Fouchet M, Journaux L, Bernard-Capel C, Ponsart C, Eggen A, Blum H, Gallard Y, Boichard D, Pailhoux E, Capitan A (2013)."Novel insights into the bovine polled phenotype and horn ontogenesis in Bovidae".PLOS ONE.8 (5) e63512.Bibcode:2013PLoSO...863512A.doi:10.1371/journal.pone.0063512.PMC3661542.PMID23717440.
^Ligon KL, Alberta JA, Kho AT, Weiss J, Kwaan MR, Nutt CL, Louis DN, Stiles CD, Rowitch DH (May 2004). "The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas".Journal of Neuropathology and Experimental Neurology.63 (5):499–509.doi:10.1093/jnen/63.5.499.PMID15198128.
^Tabu K, Ohnishi A, Sunden Y, Suzuki T, Tsuda M, Tanaka S, Sakai T, Nagashima K, Sawa H (Apr 2006). "A novel function of OLIG2 to suppress human glial tumor cell growth via p27Kip1 transactivation".Journal of Cell Science.119 (Pt 7):1433–41.doi:10.1242/jcs.02854.PMID16554441.S2CID14374119.
^Birdsall B, Griffiths DV, Roberts GC, Feeney J, Burgen A (Mar 1977). "1H nuclear magnetic resonance studies of Lactobacillus casei dihydrofolate reductase: effects of substrate and inhibitor binding on the histidine residues".Proceedings of the Royal Society of London. Series B, Biological Sciences.196 (1124):251–65.Bibcode:1977RSPSB.196..251B.doi:10.1098/rspb.1977.0040.PMID16268.S2CID1651311.
Tabu K, Ohnishi A, Sunden Y, Suzuki T, Tsuda M, Tanaka S, Sakai T, Nagashima K, Sawa H (Apr 2006). "A novel function of OLIG2 to suppress human glial tumor cell growth via p27Kip1 transactivation".Journal of Cell Science.119 (Pt 7):1433–41.doi:10.1242/jcs.02854.PMID16554441.S2CID14374119.
Ruf N, Martelli M, Weschke B, Uhlenberg B (Apr 2007). "Oligodendroglial transcription factor (OLIG1 and OLIG2) mutations are not associated with Pelizaeus-Merzbacher-like leukodystrophy".American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics.144B (3):365–6.doi:10.1002/ajmg.b.30434.PMID17171653.S2CID25663863.
