Identification of a Transcription Factor that Promotes Spermatogonial Stem Cell Establishment

Spermatogonial stem cells (SSCs) are critical for maintaining spermatogenesis throughout adult life. Little is known about how SSCs are first generated. Here, we report the identification of a transcription factor—RHOX10—that promotes the initial establishment of SSCs. We were led to this discovery because we found that conditional loss of a large X-linked gene cluster comprised of 33 related homeobox genes, including Rhox10, causes defects predicted if SSCs fail to be generated or maintained. Remarkably, KO of only Rhox10 elicits SSC-related defects indistinguishable from KO of the entire gene cluster. Using a battery of approaches, including single cell-RNAseq analysis, we determined that loss of Rhox10 causes accumulation of undifferentiated germ cells—Pro-spermatogonia (ProSG)—at a time when they normally would form SSCs. The identification of a transcription factor that drives the initial generation of SSCs has potential therapeutic applications for infertility. Overall design: Single cell RNA-seq analysis of ID4-positive testicular cells from Wildtype and Rhox10 knockout mice (Postnatal day 3 and 7)

423

Song HW, Bettegowda A, Lake BB, Zhao AH, Skarbrevik D, Babajanian E, Sukhwani M, Shum EY, Phan MH, Plank TM, Richardson ME, Ramaiah M, Sridhar V, de Rooij DG, Orwig KE, Zhang K, Wilkinson MF