Identification of SOX3 as an XX male sex reversal gene in mice and humans

Edwina Sutton, James Hughes, Stefan White, Ryohei Sekido, Jacqueline Tan, Valerie Arboleda, Nicholas Rogers, Kevin Knower, Lynn Rowley, Helen Eyre, Karine Rizzoti, Dale McAninch, Joao Goncalves, Jennie Slee, Erin Turbitt, Damien Bruno, Henrik Bengtsson, Vincent Harley, Eric Vilain, Andrew Sinclair & 2 others Robin Lovell-Badge, Paul Thomas*

*Corresponding author for this work

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and X,C females) The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sty-related HMG box-containing gene 9 (SOX9) Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis Indeed, loss-of-function mutations in SOX3 do not affect sex determination m mice or humans To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3 Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal Together, these data suggest that SOX3 and SRY are functionally interchangeable m sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

Original languageEnglish
Pages (from-to)328-341
Number of pages14
JournalThe Journal of Clinical Investigation
Volume121
Issue number1
Early online date22 Dec 2010
DOIs
Publication statusPublished - 4 Jan 2011

Keywords

  • beta-catenin
  • testis-determining gene
  • sertoli-cells
  • retinoic acid
  • sry expression
  • mammalian sex
  • mental-retardation
  • cell precursors
  • linked hypopituitarism
  • determining region

Cite this

Identification of SOX3 as an XX male sex reversal gene in mice and humans. / Sutton, Edwina; Hughes, James; White, Stefan; Sekido, Ryohei; Tan, Jacqueline; Arboleda, Valerie; Rogers, Nicholas; Knower, Kevin; Rowley, Lynn; Eyre, Helen; Rizzoti, Karine; McAninch, Dale; Goncalves, Joao; Slee, Jennie; Turbitt, Erin; Bruno, Damien; Bengtsson, Henrik; Harley, Vincent; Vilain, Eric; Sinclair, Andrew; Lovell-Badge, Robin; Thomas, Paul.

In: The Journal of Clinical Investigation, Vol. 121, No. 1, 04.01.2011, p. 328-341.

Research output: Contribution to journalArticle

Sutton, E, Hughes, J, White, S, Sekido, R, Tan, J, Arboleda, V, Rogers, N, Knower, K, Rowley, L, Eyre, H, Rizzoti, K, McAninch, D, Goncalves, J, Slee, J, Turbitt, E, Bruno, D, Bengtsson, H, Harley, V, Vilain, E, Sinclair, A, Lovell-Badge, R & Thomas, P 2011, 'Identification of SOX3 as an XX male sex reversal gene in mice and humans', The Journal of Clinical Investigation, vol. 121, no. 1, pp. 328-341. https://doi.org/10.1172/JCI42580
Sutton, Edwina ; Hughes, James ; White, Stefan ; Sekido, Ryohei ; Tan, Jacqueline ; Arboleda, Valerie ; Rogers, Nicholas ; Knower, Kevin ; Rowley, Lynn ; Eyre, Helen ; Rizzoti, Karine ; McAninch, Dale ; Goncalves, Joao ; Slee, Jennie ; Turbitt, Erin ; Bruno, Damien ; Bengtsson, Henrik ; Harley, Vincent ; Vilain, Eric ; Sinclair, Andrew ; Lovell-Badge, Robin ; Thomas, Paul. / Identification of SOX3 as an XX male sex reversal gene in mice and humans. In: The Journal of Clinical Investigation. 2011 ; Vol. 121, No. 1. pp. 328-341.
@article{59dae08994b448639297f564846a8b96,
title = "Identification of SOX3 as an XX male sex reversal gene in mice and humans",
abstract = "Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and X,C females) The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sty-related HMG box-containing gene 9 (SOX9) Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis Indeed, loss-of-function mutations in SOX3 do not affect sex determination m mice or humans To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3 Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal Together, these data suggest that SOX3 and SRY are functionally interchangeable m sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.",
keywords = "beta-catenin, testis-determining gene, sertoli-cells, retinoic acid, sry expression, mammalian sex, mental-retardation, cell precursors, linked hypopituitarism, determining region",
author = "Edwina Sutton and James Hughes and Stefan White and Ryohei Sekido and Jacqueline Tan and Valerie Arboleda and Nicholas Rogers and Kevin Knower and Lynn Rowley and Helen Eyre and Karine Rizzoti and Dale McAninch and Joao Goncalves and Jennie Slee and Erin Turbitt and Damien Bruno and Henrik Bengtsson and Vincent Harley and Eric Vilain and Andrew Sinclair and Robin Lovell-Badge and Paul Thomas",
year = "2011",
month = "1",
day = "4",
doi = "10.1172/JCI42580",
language = "English",
volume = "121",
pages = "328--341",
journal = "The Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - Identification of SOX3 as an XX male sex reversal gene in mice and humans

AU - Sutton, Edwina

AU - Hughes, James

AU - White, Stefan

AU - Sekido, Ryohei

AU - Tan, Jacqueline

AU - Arboleda, Valerie

AU - Rogers, Nicholas

AU - Knower, Kevin

AU - Rowley, Lynn

AU - Eyre, Helen

AU - Rizzoti, Karine

AU - McAninch, Dale

AU - Goncalves, Joao

AU - Slee, Jennie

AU - Turbitt, Erin

AU - Bruno, Damien

AU - Bengtsson, Henrik

AU - Harley, Vincent

AU - Vilain, Eric

AU - Sinclair, Andrew

AU - Lovell-Badge, Robin

AU - Thomas, Paul

PY - 2011/1/4

Y1 - 2011/1/4

N2 - Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and X,C females) The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sty-related HMG box-containing gene 9 (SOX9) Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis Indeed, loss-of-function mutations in SOX3 do not affect sex determination m mice or humans To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3 Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal Together, these data suggest that SOX3 and SRY are functionally interchangeable m sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

AB - Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and X,C females) The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sty-related HMG box-containing gene 9 (SOX9) Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis Indeed, loss-of-function mutations in SOX3 do not affect sex determination m mice or humans To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3 Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal Together, these data suggest that SOX3 and SRY are functionally interchangeable m sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

KW - beta-catenin

KW - testis-determining gene

KW - sertoli-cells

KW - retinoic acid

KW - sry expression

KW - mammalian sex

KW - mental-retardation

KW - cell precursors

KW - linked hypopituitarism

KW - determining region

U2 - 10.1172/JCI42580

DO - 10.1172/JCI42580

M3 - Article

VL - 121

SP - 328

EP - 341

JO - The Journal of Clinical Investigation

JF - The Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -