Retinoic acid availability drives the asynchronous initiation of spermatogonial differentiation in the mouse

Biol Reprod. 2010 Nov;83(5):783-90. doi: 10.1095/biolreprod.110.085811. Epub 2010 Jul 21.


Throughout the reproductive lifespan of most male mammals, sperm production is constant because of the regulated differentiation of spermatogonia. Retinoic acid (RA) and a downstream target, Stra8, are required for complete spermatogenesis. To examine the role of RA in initiating spermatogonial differentiation, a transgenic mouse model expressing beta-galactosidase under the control of an RA response element was used. Cells in the neonatal testis undergoing active RA signaling were visualized by beta-galactosidase activity, the relationship between RA and differentiation determined, and the role of RA-degrading enzymes in regulating RA demonstrated. Beta-galactosidase activity was found to be predominantly associated with differentiating, premeiotic germ cells and to be distributed nonuniformly throughout the seminiferous tubules. Additionally, beta-galactosidase activity in premeiotic germ cells colocalized with STRA8 protein and was induced in germ cells with exogenous RA treatment. The RA-degrading enzyme, CYP26B1, was found to have germ cell localization and nonuniform distribution between tubules via immunohistochemistry. Treatment with a CYP26 enzyme inhibitor resulted in an increased number of germ cells with both beta-galactosidase activity and STRA8 protein and an increase in the expression of genes associated with differentiation and reduced expression of a gene associated with undifferentiated germ cells. These results show the action of RA in a subset of spermatogonia leads to nonuniform initiation of differentiation throughout the neonatal testis, potentially mediated through the action of CYP26 enzymes. Thus, the presence of RA is a likely driving factor in the initiation of spermatogonial differentiation and may result in asynchronous spermatogenesis.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Aging
  • Animals
  • Animals, Newborn
  • Antigens, Differentiation / metabolism
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Down-Regulation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Genes, Reporter
  • Male
  • Mice
  • Mice, Transgenic
  • Organ Specificity
  • Proteins / metabolism
  • Retinoic Acid 4-Hydroxylase
  • Seminiferous Tubules / cytology
  • Seminiferous Tubules / drug effects
  • Seminiferous Tubules / growth & development
  • Seminiferous Tubules / metabolism
  • Signal Transduction
  • Spermatogenesis* / drug effects
  • Spermatogonia / drug effects
  • Spermatogonia / growth & development
  • Spermatogonia / physiology*
  • Testis / cytology*
  • Testis / drug effects
  • Testis / growth & development*
  • Testis / metabolism
  • Tretinoin / pharmacology*
  • Tretinoin / physiology*
  • Up-Regulation / drug effects


  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Proteins
  • Stra8 protein, mouse
  • Tretinoin
  • Cytochrome P-450 Enzyme System
  • Cyp26b1 protein, mouse
  • Retinoic Acid 4-Hydroxylase