DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation

Anna Minkina, Clinton K. Matson, Robin E. Lindeman, Norbert B. Ghyselinck, Vivian J. Bardwell, David Zarkower

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Mammalian sex determination initiates in the fetal gonad with specification of bipotential precursor cells into male Sertoli cells or female granulosa cells. This choice was long presumed to be irreversible, but genetic analysis in the mouse recently revealed that sexual fates must be maintained throughout life. Somatic cells in the testis or ovary, even in adults, can be induced to transdifferentiate to their opposite-sex equivalents by loss of a single transcription factor, DMRT1 in the testis or FOXL2 in the ovary. Here, we investigate what mechanism DMRT1 prevents from triggering transdifferentiation. We find that DMRT1 blocks testicular retinoic acid (RA) signaling from activating genes normally involved in female sex determination and ovarian development and show that inappropriate activation of these genes can drive sexual transdifferentiation. By preventing activation of potential feminizing genes, DMRT1 allows Sertoli cells to participate in RA signaling, which is essential for reproduction, without being sexually reprogrammed.

Original languageEnglish (US)
Pages (from-to)511-520
Number of pages10
JournalDevelopmental Cell
Volume29
Issue number5
DOIs
StatePublished - Jun 9 2014

Bibliographical note

Funding Information:
We thank R. Behringer, D. Largaespada, K. Parker, S. Kliewer, A. Schedl, and M. Treier for providing mice; M. Griswold and M. Wegner for antibodies; and D. Greenstein and E. Matunis for critical reading of the manuscript. We also thank K. Hogarth and M. Griswold for WIN 18,446 and much helpful advice. This work was supported by the NIH (5 RO1 GM59152 and 1 F32 GM106484), an NSF predoctoral fellowship (to C.K.M), the Minnesota Medical Foundation, and the French Agence Nationale de la Recherche under the frame program Investissements d’Avenir labelled ANR-10-LABX-0030-INRT (to N.B.G).

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