Lrh1 can help reprogram sexual cell fate and is required for Sertoli cell development and spermatogenesis in the mouse testis

Kellie S. Agrimson, Anna Minkina, Danielle Sadowski, Andrew Wheeler, Mark W. Murphy, Micah D. Gearhart, Vivian J. Bardwell, David Zarkower

Research output: Contribution to journalArticlepeer-review

Abstract

The mammalian nuclear hormone receptors LRH1 (NR5A2) and SF1 (NR5A1) are close paralogs that can bind the same DNA motif and play crucial roles in gonadal development and function. Lrh1 is essential for follicle development in the ovary and has been proposed to regulate steroidogenesis in the testis. Lrh1 expression in the testis is highly elevated by loss of the sex regulator Dmrt1, which triggers male-to-female transdifferentiation of Sertoli cells. While Sf1 has a well-defined and crucial role in testis development, no function for Lrh1 in the male gonad has been reported. Here we use conditional genetics to examine Lrh1 requirements both in gonadal cell fate reprogramming and in normal development of the three major cell lineages of the mouse testis. We find that loss of Lrh1 suppresses sexual transdifferentiation, confirming that Lrh1 can act as a key driver in reprogramming sexual cell fate. In otherwise wild-type testes, we find that Lrh1 is dispensable in Leydig cells but is required in Sertoli cells for their proliferation, for seminiferous tubule morphogenesis, for maintenance of the blood-testis barrier, for feedback regulation of androgen production, and for support of spermatogenesis. Expression profiling identified misexpressed genes likely underlying most aspects of the Sertoli cell phenotype. In the germ line we found that Lrh1 is required for maintenance of functional spermatogonia, and hence mutants progressively lose spermatogenesis. Reduced expression of the RNA binding factor Nxf2 likely contributes to the SSC defect. Unexpectedly, however, over time the Lrh1 mutant germ line recovered abundant spermatogenesis and fertility. This finding indicates that severe germ line depletion triggers a response allowing mutant spermatogonia to recover the ability to undergo complete spermatogenesis. Our results demonstrate that Lrh1, like Sf1, is an essential regulator of testis development and function but has a very distinct repertoire of functions.

Original languageEnglish (US)
Article numbere1010088
JournalPLoS genetics
Volume18
Issue number2
DOIs
StatePublished - Feb 22 2022

Bibliographical note

Funding Information:
This work was supported by University of Minnesota Medical School (https://med.umn.edu) funding to DZ and by the National Institutes of Health (https://www.nih.gov; grant numbers 5 R01 GM59152 and GM127379 to DZ and VJB, and K126M119955 to KSA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
Copyright: © 2022 Agrimson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

  • Animals
  • Female
  • Male
  • Mammals
  • Mice
  • Sertoli Cells
  • Sex Differentiation
  • Spermatogenesis/genetics
  • Spermatogonia
  • Testis/metabolism

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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