SOHLH1 and SOHLH2 coordinate spermatogonial differentiation

Dev Biol. 2012 Jan 15;361(2):301-12. doi: 10.1016/j.ydbio.2011.10.027. Epub 2011 Oct 26.


Spermatogonial self-renewal and differentiation are essential for male fertility and reproduction. We discovered that germ cell specific genes Sohlh1 and Sohlh2, encode basic helix-loop-helix (bHLH) transcriptional regulators that are essential in spermatogonial differentiation. Sohlh1 and Sohlh2 individual mouse knockouts show remarkably similar phenotypes. Here we show that SOHLH1 and SOHLH2 proteins are co-expressed in the entire spermatogonial population except in the GFRA1(+) spermatogonia, which includes spermatogonial stem cells (SSCs). SOHLH1 and SOHLH2 are expressed in both KIT negative and KIT positive spermatogonia, and overlap Ngn3/EGFP and SOX3 expression. SOHLH1 and SOHLH2 heterodimerize with each other in vivo, as well as homodimerize. The Sohlh1/Sohlh2 double mutant phenocopies single mutants, i.e., spermatogonia continue to proliferate but do not differentiate properly. Further analysis revealed that GFRA1(+) population was increased, while meiosis commenced prematurely in both single and double knockouts. Sohlh1 and Sohlh2 double deficiency has a synergistic effect on gene expression patterns as compared to the single knockouts. SOHLH proteins affect spermatogonial development by directly regulating Gfra1, Sox3 and Kit gene expression. SOHLH1 and SOHLH2 suppress genes involved in SSC maintenance, and induce genes important for spermatogonial differentiation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Differentiation* / genetics
  • Chromatin / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Knockout Techniques
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Humans
  • Male
  • Meiosis
  • Mice
  • Models, Biological
  • Mutation / genetics
  • Protein Binding
  • Protein Multimerization
  • Proto-Oncogene Proteins c-kit / metabolism
  • Spermatogonia / cytology*
  • Spermatogonia / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • Chromatin
  • Gfra1 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Sohlh1 protein, mouse
  • Sohlh2 protein, mouse
  • Proto-Oncogene Proteins c-kit