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Fine Time Course Expression Analysis Identifies Cascades of Activation and Repression and Maps a Putative Regulator of Mammalian Sex Determination

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  • Steven C Munger
  • Anirudh Natarajan
  • Loren L Looger
  • Uwe Ohler
  • Blanche Capel

Abstract

In vertebrates, primary sex determination refers to the decision within a bipotential organ precursor to differentiate as a testis or ovary. Bifurcation of organ fate begins between embryonic day (E) 11.0–E12.0 in mice and likely involves a dynamic transcription network that is poorly understood. To elucidate the first steps of sexual fate specification, we profiled the XX and XY gonad transcriptomes at fine granularity during this period and resolved cascades of gene activation and repression. C57BL/6J (B6) XY gonads showed a consistent ∼5-hour delay in the activation of most male pathway genes and repression of female pathway genes relative to 129S1/SvImJ, which likely explains the sensitivity of the B6 strain to male-to-female sex reversal. Using this fine time course data, we predicted novel regulatory genes underlying expression QTLs (eQTLs) mapped in a previous study. To test predictions, we developed an in vitro gonad primary cell assay and optimized a lentivirus-based shRNA delivery method to silence candidate genes and quantify effects on putative targets. We provide strong evidence that Lmo4 (Lim-domain only 4) is a novel regulator of sex determination upstream of SF1 (Nr5a1), Sox9, Fgf9, and Col9a3. This approach can be readily applied to identify regulatory interactions in other systems.Author Summary: The commitment of a bipotential gonad to differentiate as a testis or an ovary is governed by a dynamic transcription network that remains to be elucidated. We profiled genome-wide gene expression at

Suggested Citation

  • Steven C Munger & Anirudh Natarajan & Loren L Looger & Uwe Ohler & Blanche Capel, 2013. "Fine Time Course Expression Analysis Identifies Cascades of Activation and Repression and Maps a Putative Regulator of Mammalian Sex Determination," PLOS Genetics, Public Library of Science, vol. 9(7), pages 1-17, July.
    • Handle: RePEc:plo:pgen00:1003630
    DOI: 10.1371/journal.pgen.1003630
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    References listed on IDEAS

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    1. Ryohei Sekido & Robin Lovell-Badge, 2008. "Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer," Nature, Nature, vol. 453(7197), pages 930-934, June.
    2. Seppo Vainio & Minna Heikkilä & Andreas Kispert & Norman Chin & Andrew P. McMahon, 1999. "Female development in mammals is regulated by Wnt-4 signalling," Nature, Nature, vol. 397(6718), pages 405-409, February.
    3. Ryohei Sekido & Robin Lovell-Badge, 2008. "Erratum: Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer," Nature, Nature, vol. 456(7223), pages 824-824, December.
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    1. Kaur KK & Allahbadia G & Singh M, 2018. "Indications of feminizing Surgery in different Causes of Ambiguous Genitalia-A Mini Opinion," Global Journal of Reproductive Medicine, Juniper Publishers Inc., vol. 3(2), pages 25-28, January.
    2. Alicia Hurtado & Irene Mota-Gómez & Miguel Lao & Francisca M. Real & Johanna Jedamzick & Miguel Burgos & Darío G. Lupiáñez & Rafael Jiménez & Francisco J. Barrionuevo, 2024. "Complete male-to-female sex reversal in XY mice lacking the miR-17~92 cluster," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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