The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

Hye-Won Song; Anilkumar Bettegowda; Blue B Lake; Adrienne H Zhao; David Skarbrevik; Eric Babajanian; Meena Sukhwani; Eleen Y Shum; Mimi H Phan; Terra-Dawn M Plank; Marcy E Richardson; Madhuvanthi Ramaiah; Vaishnavi Sridhar; Dirk G de Rooij; Kyle E Orwig; Kun Zhang; Miles F Wilkinson

doi:10.1016/j.celrep.2016.08.090

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

Hye-Won Song, Anilkumar Bettegowda, Blue B Lake, Adrienne H Zhao, David Skarbrevik, Eric Babajanian, Meena Sukhwani, Eleen Y Shum, Mimi H Phan, Terra-Dawn M Plank, Marcy E Richardson, Madhuvanthi Ramaiah, Vaishnavi Sridhar, Dirk G de Rooij, Kyle E Orwig, Kun Zhang, Miles F Wilkinson

School of Medicine, Department of Reproductive Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Department of Bioengineering, University of California at San Diego, La Jolla, CA 92093, USA.
Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
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: [email protected].

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	149-164
Number of pages	16
Journal	Cell Reports
Volume	17
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2016.08.090
Publication status	Published - 27 Sept 2016

Keywords

Adult Germline Stem Cells
Animals
Gene Expression Regulation, Developmental
Genes, Developmental
Genes, X-Linked
Homeodomain Proteins
Male
Mice
Mice, Knockout
Multigene Family
Protein Isoforms
Sequence Analysis, RNA
Single-Cell Analysis
Spermatogenesis
Spermatogonia
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1016/j.celrep.2016.08.090

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Song, H.-W., Bettegowda, A., Lake, B. B., Zhao, A. H., Skarbrevik, D., Babajanian, E., Sukhwani, M., Shum, E. Y., Phan, M. H., Plank, T.-D. M., Richardson, M. E., Ramaiah, M., Sridhar, V., de Rooij, D. G., Orwig, K. E., Zhang, K., & Wilkinson, M. F. (2016). The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment. Cell Reports, 17(1), 149-164. https://doi.org/10.1016/j.celrep.2016.08.090

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abstract = "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.",

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author = "Hye-Won Song and Anilkumar Bettegowda and Lake, {Blue B} and Zhao, {Adrienne H} and David Skarbrevik and Eric Babajanian and Meena Sukhwani and Shum, {Eleen Y} and Phan, {Mimi H} and Plank, {Terra-Dawn M} and Richardson, {Marcy E} and Madhuvanthi Ramaiah and Vaishnavi Sridhar and {de Rooij}, {Dirk G} and Orwig, {Kyle E} and Kun Zhang and Wilkinson, {Miles F}",

year = "2016",

month = sep,

day = "27",

doi = "10.1016/j.celrep.2016.08.090",

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Song, H-W, Bettegowda, A, Lake, BB, Zhao, AH, Skarbrevik, D, Babajanian, E, Sukhwani, M, Shum, EY, Phan, MH, Plank, T-DM, Richardson, ME, Ramaiah, M, Sridhar, V, de Rooij, DG, Orwig, KE, Zhang, K & Wilkinson, MF 2016, 'The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment', Cell Reports, vol. 17, no. 1, pp. 149-164. https://doi.org/10.1016/j.celrep.2016.08.090

TY - JOUR

T1 - The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

AU - Song, Hye-Won

AU - Bettegowda, Anilkumar

AU - Lake, Blue B

AU - Zhao, Adrienne H

AU - Skarbrevik, David

AU - Babajanian, Eric

AU - Sukhwani, Meena

AU - Shum, Eleen Y

AU - Phan, Mimi H

AU - Plank, Terra-Dawn M

AU - Richardson, Marcy E

AU - Ramaiah, Madhuvanthi

AU - Sridhar, Vaishnavi

AU - de Rooij, Dirk G

AU - Orwig, Kyle E

AU - Zhang, Kun

AU - Wilkinson, Miles F

PY - 2016/9/27

Y1 - 2016/9/27

N2 - 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.

AB - 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.

KW - Adult Germline Stem Cells

KW - Animals

KW - Gene Expression Regulation, Developmental

KW - Genes, Developmental

KW - Genes, X-Linked

KW - Homeodomain Proteins

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Multigene Family

KW - Protein Isoforms

KW - Sequence Analysis, RNA

KW - Single-Cell Analysis

KW - Spermatogenesis

KW - Spermatogonia

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.celrep.2016.08.090

DO - 10.1016/j.celrep.2016.08.090

M3 - Article

C2 - 27681428

SN - 2211-1247

VL - 17

SP - 149

EP - 164

JO - Cell Reports

JF - Cell Reports

IS - 1

ER -

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

Abstract

Keywords

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