title: SOHLH1 and SOHLH2 coordinate spermatogonial differentiation.
abstract: 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.
authors: Magee-Womens Research Institute, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors: Hitomi
authors: H
authors: Suzuki
authors: Hyo Won
authors: HW
authors: Ahn
authors: Tianjiao
authors: T
authors: Chu
authors: Wayne
authors: W
authors: Bowden
authors: Kathrin
authors: K
authors: Gassei
authors: Kyle
authors: K
authors: Orwig
authors: Aleksandar
authors: A
authors: Rajkovic
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D006801:Humans; D008297:Male; D008540:Meiosis; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013093:Spermatogonia / Q000166:cytology* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D019009:Proto-Oncogene Proteins c-kit; C494988:Gfra1 protein, mouse; C511466:Sohlh1 protein, mouse; C515516:Sohlh2 protein, mouse