Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Identification of SOX3 as an XX male sex reversal gene in mice and humans
Edwina Sutton, … , Robin Lovell-Badge, Paul Thomas
Edwina Sutton, … , Robin Lovell-Badge, Paul Thomas
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):328-341. https://doi.org/10.1172/JCI42580.
View: Text | PDF
Research Article Development

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

  • Text
  • PDF
Abstract

Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX 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 Sry-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 in 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 in 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.

Authors

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, Robin Lovell-Badge, Paul Thomas

×

Figure 7

Expression profile of Aldh1a1/Aldh1a1 and Sox3 in XY and XX Tg/+ gonads from 11.5 to 13.5 dpc.

Options: View larger image (or click on image) Download as PowerPoint
Expression profile of Aldh1a1/Aldh1a1 and Sox3 in XY and XX Tg/+ gonads ...
(A) qRT-PCR analysis of 11.5- to 13.5-dpc gonads. Normalized expression levels of each gene are shown relative to β-actin. Two cDNA series were analyzed twice each, and error bars represent SD of the mean of the two series. (B) In situ hybridization showing Aldh1a1 expression in transverse sections of 13.5-dpc XY, XX Tg/+, and XX gonads. No signal was detected using an Aldh1a1 sense probe. (C) Transverse sections of XY, XX Tg/+, and XX 13.5-dpc gonads stained with Aldh1a1, Sox3, and DAPI. Protein expression levels are consistent with the transcript expression analysis shown in B. (D) Confocal micrograph of 13.5-dpc XX Tg/+ gonad showing the extensive overlap in Sox3 and Aldh1a1 expression. Arrows indicate Sox3/Aldh1a1-positive cells lining the testis cords. Scale bars: 100 μm.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts