SOX3 explained

Transcription factor SOX-3 is a protein that in humans is encoded by the SOX3 gene.^{[1] [2]} This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic brain development and in determination of cell fate. The encoded protein acts as a transcriptional activator.^[3]

Mutations in this gene have been associated with X-linked hypopituitarism (XH) and X-linked mental retardation. Patients with XH are male, have short stature, exhibit a mild form of mental retardation and present pan-hypopituitarism.^{[2] [4]} A duplication of the SOX3 gene has also been discovered to cause XX male sex reversal.^[5]

SRY-box transcription factor 3, SOX3, is a transcription factor that is encoded by the SOX3 gene. This gene is responsible for ensuring proper embryonic development and determining the fate of different cells. Regarding its developmental facet, SOX3, alongside other SOX transcription factors, ensures the proper formation of the hypothalamo-pituitary axis.^[6] The proper development of the hypothalamo-pituitary axis is necessary as it serves to ensure proper systemic hormonal function. When SOX3 expression is affected, the development of different structures can be affected as well. Specifically, both the hypothalamus and the pituitary gland can suffer in accomplishing proper growth. Due to this, conditions such as hypopituitarism and mental retardation are found in cases with a lack of SOX3. Also, craniofacial abnormalities can be seen as a result of a lack of the SOX3 gene. To aid in the further understanding of the SOX3 gene, mice have been used as knockout models to study the effects of the gene’s absence.^[7]

Function

SOX3 belongs to the family of SRY-related HMG-box containing genes which behave as transcription factors. SOX3 has been found to be involved in the regulation of embryonic brain development, the determination of cell fate and in XX male sex reversal.^[3]

SOX3 contains a single exon and is found in a highly conserved region of the X chromosome. The SOX3 gene shares some conservation with the SRY gene, and encodes a protein that is similar, sharing 67% amino acid identity across the DNA-binding HMG domain.^[8] This has led to the hypothesis that the SRY gene arose from SOX3 through a gain of function mutation within the proto-Y chromosome. Evidence to support this hypothesis arose from the discovery of a rare human case of XX sex reversal, that is thought to have occurred through a de novo duplication of the SOX3 gene.^[5] Such a duplication is thought to result in a gain of function expression of SOX3 in the genital ridge of the developing embryo leading to XX male sex reversal.

See also

• SOX gene family

Further reading

• Kamachi Y, Uchikawa M, Kondoh H . Pairing SOX off: with partners in the regulation of embryonic development . Trends in Genetics . 16 . 4 . 182–187 . April 2000 . 10729834 . 10.1016/S0168-9525(99)01955-1 .
• Bowles J, Schepers G, Koopman P . Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators . Developmental Biology . 227 . 2 . 239–255 . November 2000 . 11071752 . 10.1006/dbio.2000.9883 . free .
• Schepers GE, Teasdale RD, Koopman P . Twenty pairs of sox: extent, homology, and nomenclature of the mouse and human sox transcription factor gene families . Developmental Cell . 3 . 2 . 167–170 . August 2002 . 12194848 . 10.1016/S1534-5807(02)00223-X . free .
• Denny P, Swift S, Brand N, Dabhade N, Barton P, Ashworth A . A conserved family of genes related to the testis determining gene, SRY . Nucleic Acids Research . 20 . 11 . 2887 . June 1992 . 1614875 . 336939 . 10.1093/nar/20.11.2887 .
• Stevanović M, Lovell-Badge R, Collignon J, Goodfellow PN . SOX3 is an X-linked gene related to SRY . Human Molecular Genetics . 2 . 12 . 2013–2018 . December 1993 . 8111369 . 10.1093/hmg/2.12.2013 .
• Collignon J, Sockanathan S, Hacker A, Cohen-Tannoudji M, Norris D, Rastan S, Stevanovic M, Goodfellow PN, Lovell-Badge R . A comparison of the properties of Sox-3 with Sry and two related genes, Sox-1 and Sox-2 . Development . 122 . 2 . 509–520 . February 1996 . 8625802 . 10.1242/dev.122.2.509 .
• Laumonnier F, Ronce N, Hamel BC, Thomas P, Lespinasse J, Raynaud M, Paringaux C, Van Bokhoven H, Kalscheuer V, Fryns JP, Chelly J, Moraine C, Briault S . Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency . American Journal of Human Genetics . 71 . 6 . 1450–1455 . December 2002 . 12428212 . 420004 . 10.1086/344661 .
• Aota S, Nakajima N, Sakamoto R, Watanabe S, Ibaraki N, Okazaki K . Pax6 autoregulation mediated by direct interaction of Pax6 protein with the head surface ectoderm-specific enhancer of the mouse Pax6 gene . Developmental Biology . 257 . 1 . 1–13 . May 2003 . 12710953 . 10.1016/S0012-1606(03)00058-7 .
• Weiss J, Meeks JJ, Hurley L, Raverot G, Frassetto A, Jameson JL . Sox3 is required for gonadal function, but not sex determination, in males and females . Molecular and Cellular Biology . 23 . 22 . 8084–8091 . November 2003 . 14585968 . 262333 . 10.1128/MCB.23.22.8084-8091.2003 .
• Dattani MT . Borjeson-Forssman-Lehmann syndrome: a novel pituitary phenotype due to mutation in a novel gene . Journal of Pediatric Endocrinology & Metabolism . 16 . 9 . 1207–1209 . December 2003 . 14714741 . 10.1515/jpem.2003.16.9.1207 . 45542882 .
• Raverot G, Lejeune H, Kotlar T, Pugeat M, Jameson JL . X-linked sex-determining region Y box 3 (SOX3) gene mutations are uncommon in men with idiopathic oligoazoospermic infertility . The Journal of Clinical Endocrinology and Metabolism . 89 . 8 . 4146–4148 . August 2004 . 15292361 . 10.1210/jc.2004-0191 . 24592833 .
• Solomon NM, Ross SA, Morgan T, Belsky JL, Hol FA, Karnes PS, Hopwood NJ, Myers SE, Tan AS, Warne GL, Forrest SM, Thomas PQ . Array comparative genomic hybridisation analysis of boys with X linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3 . Journal of Medical Genetics . 41 . 9 . 669–678 . September 2004 . 15342697 . 1735898 . 10.1136/jmg.2003.016949 .
• Savare J, Bonneaud N, Girard F . SUMO represses transcriptional activity of the Drosophila SoxNeuro and human Sox3 central nervous system-specific transcription factors . Molecular Biology of the Cell . 16 . 6 . 2660–2669 . June 2005 . 15788563 . 1142414 . 10.1091/mbc.E04-12-1062 .

Notes and References

1. Woods KS, Cundall M, Turton J, Rizotti K, Mehta A, Palmer R, Wong J, Chong WK, Al-Zyoud M, El-Ali M, Otonkoski T, Martinez-Barbera JP, Thomas PQ, Robinson IC, Lovell-Badge R, Woodward KJ, Dattani MT . Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism . American Journal of Human Genetics . 76 . 5 . 833–849 . May 2005 . 15800844 . 1199372 . 10.1086/430134 .
2. Web site: Entrez Gene: SOX3 SRY (sex determining region Y)-box 3.
3. Bylund M, Andersson E, Novitch BG, Muhr J . Vertebrate neurogenesis is counteracted by Sox1-3 activity . Nature Neuroscience . 6 . 11 . 1162–1168 . November 2003 . 14517545 . 10.1038/nn1131 . 19874781 .
4. Barber, TM, Cheetham T, Ball SG . X-linked hypopituitarism: clinical and biochemical features of a rare cause of short stature . Endocrine Abstracts . 7 . 1 . 248 . 2004 .
5. Moalem S, Babul-Hirji R, Stavropolous DJ, Wherrett D, Bägli DJ, Thomas P, Chitayat D . XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication . American Journal of Medical Genetics. Part A . 158A . 7 . 1759–1764 . July 2012 . 22678921 . 10.1002/ajmg.a.35390 . 6220503 .
6. “SOX3 SRY-Box Transcription Factor 3 [Homo Sapiens (Human)] - Gene - NCBI.” National Center for Biotechnology Information, U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/gene/6658.
7. Rizzoti K, Brunelli S, Carmignac D, Thomas PQ, Robinson IC, Lovell-Badge R . SOX3 is required during the formation of the hypothalamo-pituitary axis . Nature Genetics . 36 . 3 . 247–255 . March 2004 . 14981518 . 10.1038/ng1309 . 20696074 . free .
8. Foster JW, Graves JA . An SRY-related sequence on the marsupial X chromosome: implications for the evolution of the mammalian testis-determining gene . Proceedings of the National Academy of Sciences of the United States of America . 91 . 5 . 1927–1931 . March 1994 . 8127908 . 43277 . 10.1073/pnas.91.5.1927 . free . 1994PNAS...91.1927F .