Sohlh2 Knockout Mice are Male Sterile Due to Degeneration of Differentiating Type-A Spermatogonia

¹ The Cecil H. & Ida Green Center for Reproductive Biology Sciences, the Departments of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390
² The Cecil H. & Ida Green Center for Reproductive Biology Sciences, the Departments of Pharmacology, and the Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390
³ The Cecil H. & Ida Green Center for Reproductive Biology Sciences, the Departments of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390

^* To whom correspondence should be addressed. E-mail: kent.hamra{at}utsouthwestern.edu.

	Abstract

The Spermatogenesis and Oogenesis-specific transcription factor, Sohlh2, is normally expressed only in pre-meiotic germ cells. In this study, Sohlh2, plus several other germ cell transcripts were found to be induced in mouse embryonic stem cells when cultured on a feeder cell line that over-expresses BMP4. To study the function of Sohlh2 in germ cells, we generated mice harboring null alleles of Sohlh2. Male Sohlh2-deficient mice were infertile due to a block in spermatogenesis. Though normal prior to birth, Sohlh2-null mice had reduced numbers of intermediate and type-B spermatogonia by postnatal day 7. By day 10, development to the pre-leptotene spermatocyte stage was severely disrupted, rendering seminiferous tubules with only Sertoli cells, undifferentiated spermatogonia and degenerating colonies of differentiating spermatogonia. Degenerating cells resembled type-A2 spermatogonia, and accumulated in M-phase prior to death. A similar phenotype was observed in Sohlh2-null mice on postnatal days 14, 21, 35, 49, 68 and 151. In adult Sohlh2-mutant mice, the ratio of undifferentiated type-A spermatogonia (DAZL+/PLZF+) to differentiating type-A spermatogonia (DAZL+/PLZF-) was twice normal levels. In culture, undifferentiated type-A spermatogonia isolated from Sohlh2-null mice proliferated normally, but linked the mutant phenotype to aberrant cell surface expression of the receptor-tyrosine kinase, cKit. Thus, Sohlh2 is required for progression of differentiating type-A spermatogonia into type-B spermatogonia. One conclusion originating from these studies would be that testicular factors normally regulate the viability of differentiating spermatogonia by signaling through Sohlh2. This would provide a crucial check-point to optimize the numbers of spermatocytes entering meiosis during each cycle of spermatogenesis.