OLIG2

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Oligodendrocyte lineage transcription factor 2
Identifiers
Symbols OLIG2 ; BHLHB1; OLIGO2; PRKCBP2; RACK17; bHLHe19
External IDs OMIM606386 MGI1355331 HomoloGene4241 GeneCards: OLIG2 Gene
RNA expression pattern
PBB GE OLIG2 213824 at tn.png
PBB GE OLIG2 213825 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 10215 50913
Ensembl ENSG00000205927 ENSMUSG00000039830
UniProt Q13516 Q9EQW6
RefSeq (mRNA) NM_005806 NM_016967
RefSeq (protein) NP_005797 NP_058663
Location (UCSC) Chr 21:
34.4 – 34.4 Mb
Chr 16:
91.23 – 91.23 Mb
PubMed search [1] [2]

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, 32kDa in size and contains 1 basic helix-loop-helix DNA-binding domain.[1] It’s one of the three members of the bHLH family. The other two members are OLIG1 and OLIG3. The expression of OLIG2 is mostly restricted in central nervous system, 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 differentiation, as well as its role in sustaining replication in early development. It’s mainly involved in diseases such as brain tumor and Down syndrome.

Function[edit]

OLIG2 is mostly expressed in restricted domains of the brain and spinal cord ventricular zone which give rise to oligodendrocytes and specific types of neurons. In the spinal cord the region of Olig2 expression sequentially generates motoneurons and oligodendrocytes, and is essential for motor neuron and oligodendrocyte fate specification and controlling cell proliferation and differentiation. In the early embryo development, OLIG2 first directs motor neuron fate by establishing a ventral domain of motor neuron progenitors and promoting neuronal differentiation. OLIG2 will then switch 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 replication. This side of anti-neurogenicity of OLIG2 later plays a bigger role in malignancies like glioma.[2]

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.[3] Phosphorylation at a triple serine motif (Ser10, Ser13 and Ser14) on the other hand was shown to regulate the proliferative function of OLIG2.[4] Another phosphorylation site Ser147 predicted by bioinformatics was found to regulate motor neuron development by regulating the binding between OLIG2 and NGN2.[5] Further, OLIG2 contains a ST box composed of a string of 12 contiguous serine and threonine residues at position Ser77-Ser88. It’s believed that phosphorylation at ST box is biologically functional,[6] yet the role of it still remains to be elucidated in vivo.[7]

Clinical Significance[edit]

OLIG2 in Cancer[edit]

OLIG2 is well recognized for its importance in cancer research, particularly in brain tumors and leukemia. OLIG2 is universally expressed in glioblastoma and other diffuse gliomas (astrocytomas, oligodendrogliomas and oligoastrocytomas), and is a useful positive diagnostic marker of these brain tumors.[8] In particular, OLIG2 is selectively expressed in a subgroup of glioma cells that are highly tumorigenic,[9] and is shown to be required for proliferation of human glioma cells implanted in the brain of severe combined immunodeficiency (SCID) mice.[10]

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’s believed that OLIG2 promotes neural stem cell and progenitor cell proliferation by opposing p53 pathway, which potentially contributes to glioma progression. OLIG2 has been shown to directly repress the p53 tumor-suppressor pathway effector p21WAF1/CIP1,[11] suppress p53 acetylation and impede the binding of p53 to several enhancer sites.[12] It’s 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.[13] 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 p27Kip1 gene[14] and can inhibit the motility of the cell by activating RhoA.[15]

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.[16] 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 cell lines.[17] It also has been shown that up-regulation of OLIG2 together with LMO1 and Notch1 helps to provide proliferation signals.

OLIG2 in Neural Diseases[edit]

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.[18] The association between OLIG2 and neural diseases (i.e. schizophrenia 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.[19][20]

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.[21] OLIG2 was also implicated in generating reactive astrocytes possibly in a transient re-expression manner, but the mechanisms are unclear.[22]

References[edit]

  1. ^ http://atlasgeneticsoncology.org/Genes/OLIG2ID236.html.  Missing or empty |title= (help)
  2. ^ Gaber, Z. B.; Novitch, B. G. (2011). "All the Embryo's a Stage, and Olig2 in Its Time Plays Many Parts". Neuron 69 (5): 833–835. doi:10.1016/j.neuron.2011.02.037. PMID 21382543.  edit
  3. ^ Setoguchi, T.; Kondo, T. (2004). "Nuclear export of OLIG2 in neural stem cells is essential for ciliary neurotrophic factor-induced astrocyte differentiation". The Journal of Cell Biology 166 (7): 963–968. doi:10.1083/jcb.200404104. PMC 2172021. PMID 15452140.  edit
  4. ^ Sun, Y.; Meijer, D. H.; Alberta, J. A.; Mehta, S.; Kane, M. F.; Tien, A. C.; Fu, H.; Petryniak, M. A.; Potter, G. B.; Liu, Z.; Powers, J. F.; Runquist, I.  S.; Rowitch, D. H.; Stiles, C. D. (2011). "Phosphorylation State of Olig2 Regulates Proliferation of Neural Progenitors". Neuron 69 (5): 906–917. doi:10.1016/j.neuron.2011.02.005. PMC 3065213. PMID 21382551.  edit
  5. ^ Li, H.; Paes De Faria, J.; Andrew, P.; Nitarska, J.; Richardson, W. D. (2011). "Phosphorylation Regulates OLIG2 Cofactor Choice and the Motor Neuron-Oligodendrocyte Fate Switch". Neuron 69 (5): 918–929. doi:10.1016/j.neuron.2011.01.030. PMC 3093612. PMID 21382552.  edit
  6. ^ Huillard, E.; Ziercher, L.; Blond, O.; Wong, M.; Deloulme, J. C.; Souchelnytskyi, S.; Baudier, J.; Cochet, C.; Buchou, T. (2010). "Disruption of CK2  in Embryonic Neural Stem Cells Compromises Proliferation and Oligodendrogenesis in the Mouse Telencephalon". Molecular and Cellular Biology 30 (11): 2737–2749. doi:10.1128/MCB.01566-09. PMC 2876519. PMID 20368359.  edit
  7. ^ Sun, Y.; Meijer, D. H.; Alberta, J. A.; Mehta, S.; Kane, M. F.; Tien, A. C.; Fu, H.; Petryniak, M. A.; Potter, G. B.; Liu, Z.; Powers, J. F.; Runquist, I.  S.; Rowitch, D. H.; Stiles, C. D. (2011). "Phosphorylation State of Olig2 Regulates Proliferation of Neural Progenitors". Neuron 69 (5): 906–917. doi:10.1016/j.neuron.2011.02.005. PMC 3065213. PMID 21382551.  edit
  8. ^ Ligon, K. L.; Alberta, J. A.; Kho, A. T.; Weiss, J.; Kwaan, M. R.; Nutt, C. L.; Louis, D. N.; Stiles, C. D.; Rowitch, D. H. (2004). "The oligodendroglial lineage marker OLIG2 is universally expressed in diffuse gliomas". Journal of neuropathology and experimental neurology 63 (5): 499–509. PMID 15198128.  edit
  9. ^ Ligon, K. L.; Huillard, E.; Mehta, S.; Kesari, S.; Liu, H.; Alberta, J. A.; Bachoo, R. M.; Kane, M.; Louis, D. N.; Depinho, R. A.; Anderson, D. J.; Stiles, C. D.; Rowitch, D. H. (2007). "Olig2-Regulated Lineage-Restricted Pathway Controls Replication Competence in Neural Stem Cells and Malignant Glioma". Neuron 53 (4): 503–517. doi:10.1016/j.neuron.2007.01.009. PMC 1810344. PMID 17296553.  edit
  10. ^ Mehta, S.; Huillard, E.; Kesari, S.; Maire, C. L.; Golebiowski, D.; Harrington, E. P.; Alberta, J. A.; Kane, M. F.; Theisen, M.; Ligon, K. L.; Rowitch, D. H.; Stiles, C. D. (2011). "The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant Glioma". Cancer Cell 19 (3): 359–371. doi:10.1016/j.ccr.2011.01.035. PMC 3070398. PMID 21397859.  edit
  11. ^ Ligon, K. L.; Huillard, E.; Mehta, S.; Kesari, S.; Liu, H.; Alberta, J. A.; Bachoo, R. M.; Kane, M.; Louis, D. N.; Depinho, R. A.; Anderson, D. J.; Stiles, C. D.; Rowitch, D. H. (2007). "Olig2-Regulated Lineage-Restricted Pathway Controls Replication Competence in Neural Stem Cells and Malignant Glioma". Neuron 53 (4): 503–517. doi:10.1016/j.neuron.2007.01.009. PMC 1810344. PMID 17296553.  edit
  12. ^ Mehta, S.; Huillard, E.; Kesari, S.; Maire, C. L.; Golebiowski, D.; Harrington, E. P.; Alberta, J. A.; Kane, M. F.; Theisen, M.; Ligon, K. L.; Rowitch, D. H.; Stiles, C. D. (2011). "The Central Nervous System-Restricted Transcription Factor Olig2 Opposes p53 Responses to Genotoxic Damage in Neural Progenitors and Malignant Glioma". Cancer Cell 19 (3): 359–371. doi:10.1016/j.ccr.2011.01.035. PMC 3070398. PMID 21397859.  edit
  13. ^ Sun, Y.; Meijer, D. H.; Alberta, J. A.; Mehta, S.; Kane, M. F.; Tien, A. C.; Fu, H.; Petryniak, M. A.; Potter, G. B.; Liu, Z.; Powers, J. F.; Runquist, I.  S.; Rowitch, D. H.; Stiles, C. D. (2011). "Phosphorylation State of Olig2 Regulates Proliferation of Neural Progenitors". Neuron 69 (5): 906–917. doi:10.1016/j.neuron.2011.02.005. PMC 3065213. PMID 21382551.  edit
  14. ^ Tabu, K.; Ohnishi, A.; Sunden, Y.; Suzuki, T.; Tsuda, M.; Tanaka, S.; Sakai, T.; Nagashima, K.; Sawa, H. (2006). "A novel function of OLIG2 to suppress human glial tumor cell growth via p27Kip1 transactivation". Journal of Cell Science 119 (7): 1433–1441. doi:10.1242/jcs.02854. PMID 16554441.  edit
  15. ^ Tabu, K.; Ohba, Y.; Suzuki, T.; Makino, Y.; Kimura, T.; Ohnishi, A.; Sakai, M.; Watanabe, T.; Tanaka, S.; Sawa, H. (2007). "Oligodendrocyte Lineage Transcription Factor 2 Inhibits the Motility of a Human Glial Tumor Cell Line by Activating RhoA". Molecular Cancer Research 5 (10): 1099–1109. doi:10.1158/1541-7786.MCR-07-0096. PMID 17951409.  edit
  16. ^ Birdsall, B.; Griffiths, D. V.; Roberts, G. C.; Feeney, J.; Burgen, A. (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, Containing papers of a Biological character. Royal Society (Great Britain) 196 (1124): 251–265. doi:10.1098/rspb.1977.0040. PMID 16268.  edit
  17. ^ Lin, Y. -W.; Deveney, R.; Barbara, M.; Iscove, N. N.; Nimer, S. D.; Slape, C.; Aplan, P. D. (2005). "OLIG2 (BHLHB1), a bHLH Transcription Factor, Contributes to Leukemogenesis in Concert with LMO1". Cancer Research 65 (16): 7151–7158. doi:10.1158/0008-5472.CAN-05-1400. PMC 1681523. PMID 16103065.  edit
  18. ^ Chakrabarti, L.; Best, T. K.; Cramer, N. P.; Carney, R. S. E.; Isaac, J. T. R.; Galdzicki, Z.; Haydar, T. F. (2010). "Olig1 and Olig2 triplication causes developmental brain defects in Down syndrome". Nature Neuroscience 13 (8): 927–934. doi:10.1038/nn.2600. PMC 3249618. PMID 20639873.  edit
  19. ^ Georgieva, L.; Moskvina, V.; Peirce, T.; Norton, N.; Bray, N. J.; Jones, L.; Holmans, P.; MacGregor, S.; Zammit, S.; Wilkinson, J.; Williams, H.; Nikolov, I.; Williams, N.; Ivanov, D.; Davis, K. L.; Haroutunian, V.; Buxbaum, J. D.; Craddock, N.; Kirov, G.; Owen, M. J.; o’Donovan, M. C. (2006). "Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia". Proceedings of the National Academy of Sciences 103 (33): 12469–12474. doi:10.1073/pnas.0603029103. PMC 1567903. PMID 16891421.  edit
  20. ^ Sims, R.; Hollingworth, P.; Moskvina, V.; Dowzell, K.; O'Donovan, M. C.; Powell, J.; Lovestone, S.; Brayne, C.; Rubinsztein, D.; Owen, M. J.; Williams, J.; Abraham, R. (2009). "Evidence that variation in the oligodendrocyte lineage transcription factor 2 (OLIG2) gene is associated with psychosis in Alzheimer's disease". Neuroscience Letters 461 (1): 54–59. doi:10.1016/j.neulet.2009.05.051. PMID 19477230.  edit
  21. ^ Buffo, A.; Vosko, M. R.; Ertürk, D.; Hamann, G. F.; Jucker, M.; Rowitch, D.; Götz, M. (2005). "Expression pattern of the transcription factor Olig2 in response to brain injuries: Implications for neuronal repair". Proceedings of the National Academy of Sciences 102 (50): 18183–18188. doi:10.1073/pnas.0506535102. PMC 1312388. PMID 16330768.  edit
  22. ^ Buffo, A.; Rite, I.; Tripathi, P.; Lepier, A.; Colak, D.; Horn, A. -P.; Mori, T.; Gotz, M. (2008). "Origin and progeny of reactive gliosis: A source of multipotent cells in the injured brain". Proceedings of the National Academy of Sciences 105 (9): 3581–3586. doi:10.1073/pnas.0709002105. PMC 2265175. PMID 18299565.  edit

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.