Fetal Leydig Cells Persist as an Androgen-Independent Subpopulation in the Postnatal Testis

Mol Endocrinol. 2015 Nov;29(11):1581-93. doi: 10.1210/me.2015-1200. Epub 2015 Sep 24.

Abstract

Two distinct types of Leydig cells emerge during the development of eutherian mammals. Fetal Leydig cells (FLCs) appear shortly after gonadal sex differentiation, and play a crucial role in masculinization of male fetuses. Meanwhile, adult Leydig cells (ALCs) emerge after birth and induce the secondary male-specific sexual maturation by producing testosterone. Previous histological studies suggested that FLCs regress completely soon after birth. Furthermore, gene disruption studies indicated that androgen signaling is dispensable for FLC differentiation but indispensable for postnatal ALC differentiation. Here, we performed lineage tracing of FLCs using a FLC enhancer of the Ad4BP/SF-1 (Nr5a1) gene and found that FLCs persist in the adult testis. Given that postnatal FLCs expressed androgen receptor (AR) as well as LH receptor (LuR), the effects of AR disruption on FLCs and ALCs were analyzed by crossing AR knockout (KO) mice with FLC-specific enhanced green fluorescent protein (EGFP) mice. Moreover, to eliminate the influence of elevated LH levels in ARKO mice, LuRKO mice and AR/LuR double-KO mice were analyzed. The proportion of ALCs to postnatal FLCs was decreased in ARKO mice, and the effect was augmented in the double-KO mice, suggesting that androgen signaling plays important roles in ALCs, but not in FLCs. Finally, ARKO was achieved in an FLC-specific manner (FLCARKO mice), but the FLC number and gene expression pattern appeared unaffected. These findings support the conclusion that FLCs persist as an androgen-independent Leydig subpopulation in the postnatal testis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism*
  • Animals
  • Cell Differentiation / physiology
  • Cell Lineage
  • Embryo, Mammalian / embryology
  • Gene Expression Regulation, Developmental
  • Green Fluorescent Proteins / genetics
  • Leydig Cells / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Androgen / biosynthesis
  • Receptors, Androgen / genetics*
  • Receptors, LH / biosynthesis
  • Receptors, LH / genetics*
  • Signal Transduction
  • Steroidogenic Factor 1 / genetics
  • Testis / cytology
  • Testis / embryology*
  • Testosterone / metabolism

Substances

  • Androgens
  • Receptors, Androgen
  • Receptors, LH
  • Steroidogenic Factor 1
  • enhanced green fluorescent protein
  • steroidogenic factor 1, mouse
  • Green Fluorescent Proteins
  • Testosterone

Grants and funding

This work was supported by Japan Society for the Promotion of Science KAKENHI Grants 23590339 and 26670145 (to Y.S.) and 21249018 (K.-i.M.); Ministry of Education, Culture, Sports, Science, and Technology, Japan KAKENHI Grants 23116707 (to Y.S.) and 22132002 (K.-i.M.); Takeda Science Foundation; and Yamaguchi Endocrine Research Foundation.