Retinoic Acid Antagonizes Testis Development in Mice

Josephine Bowles, Chun Wei Feng, Jessica Ineson, Kim Miles, Cassy M. Spiller, Vincent R. Harley, Andrew H. Sinclair, Peter Koopman

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

Abstract

Mammalian sex determination depends on a complex interplay of signals that promote the bipotential fetal gonad to develop as either a testis or an ovary, but the details are incompletely understood. Here, we investigated whether removal of the signaling molecule retinoic acid (RA) by the degradative enzyme CYP26B1 is necessary for proper development of somatic cells of the testes. Gonadal organ culture experiments suggested that RA promotes expression of some ovarian markers and suppresses expression of some testicular markers, acting downstream of Sox9. XY Cyp26b1-null embryos, in which endogenous RA is not degraded, develop mild ovotestes, but more important, steroidogenesis is impaired and the reproductive tract feminized. Experiments involving purified gonadal cells showed that these effects are independent of germ cells and suggest the direct involvement of the orphan nuclear receptor DAX1. Our results reveal that active removal of endogenous RA is required for normal testis development in the mouse. Bowles et al. show that XY mouse embryos lacking the retinoic acid (RA)-degrading enzyme CYP26B1 develop ovotestes and a feminized reproductive tract. These results implicate altered RA metabolism as a possible cause of environmental endocrine disruption and genetic disorders of sex development.

Original languageEnglish
Pages (from-to)1330-1341
Number of pages12
JournalCell Reports
Volume24
Issue number5
DOIs
Publication statusPublished - 31 Jul 2018
Externally publishedYes

Keywords

  • CYP26B1
  • Dax1
  • ovary
  • retinoic acid
  • secondary sex determination
  • sex determination
  • steroidogenesis
  • testis

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