NOTCH1 gain of function in germ cells causes failure of spermatogenesis in male mice

PLoS One. 2013 Jul 30;8(7):e71213. doi: 10.1371/journal.pone.0071213. Print 2013.

Abstract

NOTCH1 is a member of the NOTCH receptor family, a group of single-pass trans-membrane receptors. NOTCH signaling is highly conserved in evolution and mediates communication between adjacent cells. NOTCH receptors have been implicated in cell fate determination, as well as maintenance and differentiation of stem cells. In the mammalian testis expression of NOTCH1 in somatic and germ cells has been demonstrated, however its role in spermatogenesis was not clear. To study the significance of NOTCH1 in germ cells, we applied a cre/loxP approach in mice to induce NOTCH1 gain- or loss-of function specifically in male germ cells. Using a Stra8-icre transgene we produced mice with conditional activation of the NOTCH1 intracellular domain (NICD) in germ cells. Spermatogenesis in these mutants was progressively affected with age, resulting in decreased testis weight and sperm count. Analysis of downstream target genes of NOTCH1 signaling showed an increased expression of Hes5, with a reduction of the spermatogonial differentiation marker, Neurog3 expression in the mutant testis. Apoptosis was significantly increased in mouse germ cells with the corresponding elevation of pro-apoptotic Trp53 and Trp63 genes' expression. We also showed that the conditional germ cell-specific ablation of Notch1 had no effect on spermatogenesis or male fertility. Our data suggest the importance of NOTCH signaling regulation in male germ cells for their survival and differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Fertility / genetics
  • Gene Deletion
  • Gene Expression
  • Gene Expression Regulation
  • Gene Order
  • Genetic Vectors / genetics
  • Germ Cells / metabolism*
  • Male
  • Mice
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism*
  • Signal Transduction
  • Spermatogenesis / genetics*
  • Testis / cytology
  • Testis / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Neurog3 protein, mouse
  • Receptor, Notch1

Grant support

Supported by the Herbert Wertheim College of Medicine, Florida International University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.