Periodic production of retinoic acid by meiotic and somatic cells coordinates four transitions in mouse spermatogenesis

Proc Natl Acad Sci U S A. 2017 Nov 21;114(47):E10132-E10141. doi: 10.1073/pnas.1710837114. Epub 2017 Nov 6.

Abstract

Mammalian spermatogenesis is an elaborately organized differentiation process, starting with diploid spermatogonia, which include germ-line stem cells, and ending with haploid spermatozoa. The process involves four pivotal transitions occurring in physical proximity: spermatogonial differentiation, meiotic initiation, initiation of spermatid elongation, and release of spermatozoa. We report how the four transitions are coordinated in mice. Two premeiotic transitions, spermatogonial differentiation and meiotic initiation, were known to be coregulated by an extrinsic signal, retinoic acid (RA). Our chemical manipulations of RA levels in mouse testes now reveal that RA also regulates the two postmeiotic transitions: initiation of spermatid elongation and spermatozoa release. We measured RA concentrations and found that they changed periodically, as also reflected in the expression patterns of an RA-responsive gene, STRA8; RA levels were low before the four transitions, increased when the transitions occurred, and remained elevated thereafter. We found that pachytene spermatocytes, which express an RA-synthesizing enzyme, Aldh1a2, contribute directly and significantly to RA production in testes. Indeed, chemical and genetic depletion of pachytene spermatocytes revealed that RA from pachytene spermatocytes was required for the two postmeiotic transitions, but not for the two premeiotic transitions. We conclude that the premeiotic transitions are coordinated by RA from Sertoli (somatic) cells. Once germ cells enter meiosis, pachytene spermatocytes produce RA to coordinate the two postmeiotic transitions. In combination, these elements underpin the spatiotemporal coordination of spermatogenesis and ensure its prodigious output in adult males.

Keywords: mouse; retinoic acid; spermatogenesis; testis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Aldehyde Dehydrogenase / genetics*
  • Aldehyde Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Cell Differentiation
  • Gene Expression Regulation, Developmental*
  • Male
  • Meiosis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pachytene Stage
  • Retinal Dehydrogenase
  • Signal Transduction
  • Spermatids / cytology
  • Spermatids / growth & development
  • Spermatids / metabolism
  • Spermatocytes / cytology
  • Spermatocytes / growth & development
  • Spermatocytes / metabolism
  • Spermatogenesis / genetics*
  • Spermatogonia / cytology
  • Spermatogonia / growth & development
  • Spermatogonia / immunology
  • Spermatozoa / cytology
  • Spermatozoa / growth & development
  • Spermatozoa / metabolism*
  • Testis / cytology
  • Testis / growth & development
  • Testis / metabolism
  • Tretinoin / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Stra8 protein, mouse
  • Tretinoin
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • Aldh1a2 protein, mouse
  • Retinal Dehydrogenase