MicroRNA 146 (Mir146) modulates spermatogonial differentiation by retinoic acid in mice

Jessica M. Huszar, Christopher J. Payne*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Impaired biogenesis of microRNAs disrupts spermatogenesis and leads to infertility in male mice. Spermatogonial differen- tiation is a key step in spermatogenesis, yet the mechanisms that control this event remain poorly defined. In this study, we discovered microRNA 146 (Mir146) to be highly regulated during spermatogonial differentiation, a process dependent on retinoic acid (RA) signaling. Mir146 transcript levels were diminished nearly 180-fold in differentiating spermatogonia when compared with undifferentiated spermatogonia. Luciferase assays revealed the direct binding of Mir146 to the 30 untranslated region of the mediator complex subunit 1 (Med1), a coregulator of retinoid receptors (RARs and RXRs). Overex- pression of Mir146 in cultured undifferentiated spermatogonia reduced Med1 transcript levels, as well as those of differentiation marker kit oncogene (Kit). MED1 protein was also diminished. Conversely, inhibition of Mir146 increased the levels of Kit. When undifferentiated spermatogonia were exposed to RA, Mir146 was downregulated along with a marker for undifferentiated germ cells, zinc finger and BTB domain containing 16 (Zbtb16; Plzf); Kit was upregulated. Overexpres- sion of Mir146 in RA-treated spermatogonia inhibited the upregulation of Kit, stimulated by retinoic acid gene 8 (Stra8), and spermatogenesis- and oogenesis-specific basic helix-loop- helix 2 (Sohlh2). Inhibition of Mir146 in RA-treated spermato- gonia greatly enhanced the upregulation of these genes. We conclude that Mir146 modulates the effects of RA on spermato- gonial differentiation.

Original languageEnglish (US)
Article number15
JournalBiology of reproduction
Volume88
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Med1
  • MicroRNA
  • Mir146
  • Retinoic acid
  • Spermatogonial differentiation

ASJC Scopus subject areas

  • Reproductive Medicine
  • Cell Biology

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