The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment.
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.
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Hye-Won
HW
Song
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Anilkumar
A
Bettegowda
Department of Bioengineering, University of California at San Diego, La Jolla, CA 92093, USA.
Blue B
BB
Lake
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Adrienne H
AH
Zhao
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
David
D
Skarbrevik
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Eric
E
Babajanian
Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
Meena
M
Sukhwani
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Eleen Y
EY
Shum
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Mimi H
MH
Phan
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Terra-Dawn M
TM
Plank
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Marcy E
ME
Richardson
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Madhuvanthi
M
Ramaiah
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Vaishnavi
V
Sridhar
Reproductive Biology Group, Division of Developmental Biology, Faculty of Science, Department of Biology, Utrecht University, 3584 CH Utrecht, the Netherlands.
Dirk G
DG
de Rooij
Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
Kyle E
KE
Orwig
Department of Bioengineering, University of California at San Diego, La Jolla, CA 92093, USA.
Kun
K
Zhang
School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: mfwilkinson@ucsd.edu.
Miles F
MF
Wilkinson
D000072956:Adult Germline Stem Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D018507:Gene Expression Regulation, Developmental; D050437:Genes, Developmental; D050172:Genes, X-Linked; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis; D013091:Spermatogenesis / Q000235:genetics*; D013093:Spermatogonia / Q000166:cytology / Q000378:metabolism*
D018398:Homeodomain Proteins; D020033:Protein Isoforms; C574602:Rhox10 protein, mouse
Rhox; germ cell; germ line stem cell; gonocytes; homeobox; prospermatogonia; spermatogenesis; spermatogonia; spermatogonial stem cells; transcription factor
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