School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Anilkumar Bettegowda
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Blue B. Lake
Department of Bioengineering, University of California at San Diego, La Jolla, CA 92093, USA
Adrienne H. Zhao
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
David Skarbrevik
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Eric Babajanian
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Meena Sukhwani
Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
Eleen Y. Shum
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Mimi H. Phan
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Terra-Dawn M. Plank
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Marcy E. Richardson
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Madhuvanthi Ramaiah
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Vaishnavi Sridhar
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
Dirk G. de Rooij
Reproductive Biology Group, Division of Developmental Biology, Faculty of Science, Department of Biology, Utrecht University, 3584 CH Utrecht, the Netherlands
Kyle E. Orwig
Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, PA 15213, USA
Kun Zhang
Department of Bioengineering, University of California at San Diego, La Jolla, CA 92093, USA
Miles F. Wilkinson
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA
The developmental origins of most adult stem cells are poorly understood. Here, we report the identification of a transcription factor—RHOX10—critical for the initial establishment of spermatogonial stem cells (SSCs). Conditional loss of the entire 33-gene X-linked homeobox gene cluster that includes Rhox10 causes progressive spermatogenic decline, a phenotype indistinguishable from that caused by loss of only Rhox10. We demonstrate that this phenotype results from dramatically reduced SSC generation. By using a battery of approaches, including single-cell-RNA sequencing (scRNA-seq) analysis, we show that Rhox10 drives SSC generation by promoting pro-spermatogonia differentiation. Rhox10 also regulates batteries of migration genes and promotes the migration of pro-spermatogonia into the SSC niche. The identification of an X-linked homeobox gene that drives the initial generation of SSCs has implications for the evolution of X-linked gene clusters and sheds light on regulatory mechanisms influencing adult stem cell generation in general.
