RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment Through A Transcription Factor Signaling Cascade
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ABSTRACT:
PROVIDER: PRJNA694173 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13510500.fastq.gz | Fastqsanger.gz | |||
| SRR13510501.fastq.gz | Fastqsanger.gz | |||
| SRR13510502.fastq.gz | Fastqsanger.gz | |||
| SRR13510503.fastq.gz | Fastqsanger.gz | |||
| SRR13510504.fastq.gz | Fastqsanger.gz |
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Project description:Spermatogonial stem cells (SSCs) are essential for male fertility. Here, we report that mouse SSC generation is driven by a transcription factor (TF) cascade controlled by the homeobox protein, RHOX10, which acts by stimulating the differentiation of SSC precursors called pro-spermatogonia (ProSG). We identify genes regulated by RHOX10 in ProSG in vivo, and define direct RHOX10-target genes using several approaches, including a rapid temporal induction assay we design: iSLAMseq. Together, these approaches identify temporal waves of direct targets, as well as secondary-target genes. Many of the RHOX10-regulated genes encode proteins with known roles in SSCs. Using an in vitro ProSG differentiation assay that we develop, we find that RHOX10 promotes mouse ProSG differentiation through a conserved transcriptional cascade involving the key germ-cell TFs DMRT1 and ZBTB16. Our study gives important insights into germ cell development and provides a blueprint for how to define TF cascades.
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Project description: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.
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Project description:Spermatogonial stem cells (SSCs) are essential for male fertility. Here, we report that mouse SSC generation is driven by a transcription factor (TF) cascade controlled by the homeobox protein, RHOX10, which acts by driving the differentiation of SSC precursors called pro-spermatogonia (ProSG). We identify genes regulated by RHOX10 in ProSG in vivo and define direct RHOX10-target genes using several approaches, including a rapid temporal induction assay: iSLAMseq. Together, these approaches identify temporal waves of RHOX10 direct targets, as well as RHOX10 secondary-target genes. Many of the RHOX10-regulated genes encode proteins with known roles in SSCs. Using an in vitro ProSG differentiation assay, we find that RHOX10 promotes mouse ProSG differentiation through a conserved transcriptional cascade involving the key germ-cell TFs DMRT1 and ZBTB16. Our study gives important insights into germ cell development and provides a blueprint for how to define TF cascades.
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Project description: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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