Rhox8 Ablation in the Sertoli Cells Using a Tissue-Specific RNAi Approach Results in Impaired Male Fertility in Mice1

Welborn, Joshua P.; Davis, Matthew; Ebers, Steven; Stodden, Genna R.; Hayashi, Kanako; Cheatwood, Joseph L.; Rao, Manjeet K.; MacLean, James A.

doi:10.1095/biolreprod.114.124834

Cited by 27 publications

(36 citation statements)

References 45 publications

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“…Other members of this 33-gene cluster are likely to function in other aspects of spermatogenesis. The Sertoli cell-expressed Rhox genes, Rhox5 and Rhox8 , have been shown to promote germ cell survival, the generation of normal numbers of motile sperm, and male fertility, in part through regulation of androgen-dependent events in Sertoli cells (Hu et al, 2010; Maclean et al, 2005; Welborn et al, 2015). Germ cell-expressed Rhox genes in addition to Rhox10 are likely to also have roles in spermatogenesis, based on our finding that mice lacking the entire Rhox cluster in germ cells have post-SSC defects not observed in Rhox10 -KO mice (H.W.S., unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

Song

Bettegowda

Lake³

et al. 2016

Cell Reports

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Summary The developmental origins of most adult stem cells are poorly understood. Here, we report the identification of a transcription factor—RHOX10—that is 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. Using a battery of approaches, including single cell-RNAseq (scRNAseq) 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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Section: Discussionmentioning

confidence: 99%

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

Song

Bettegowda

Lake³

et al. 2016

Cell Reports

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“…They encode transcription factors that are selectively expressed in the reproductive tract; in humans this gene cluster is mainly expressed in male and female germ cells (12)(13)(14)(15). Mice with loss or depletion of Rhox genes exhibit male reproductive defects (12,20) and human RHOX gene promoters are hypermethylated in sperm from men with abnormal semen parameters (14). Here, we report the identification of specific genes regulated by the human RHOX transcription factors and we identify specific mutations in RHOX genes that disrupt their ability to regulate transcription.…”

Section: Discussionmentioning

confidence: 99%

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann

Tüttelmann²,

Dworniczak³

et al. 2016

Hum. Mol. Genet.

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The X-linked reproductive homeobox (RHOX) gene cluster encodes transcription factors preferentially expressed in reproductive tissues. This gene cluster has important roles in male fertility based on phenotypic defects of Rhox-mutant mice and the finding that aberrant RHOX promoter methylation is strongly associated with abnormal human sperm parameters. However, little is known about the molecular mechanism of RHOX function in humans. Using gene expression profiling, we identified genes regulated by members of the human RHOX gene cluster. Some genes were uniquely regulated by RHOXF1 or RHOXF2/2B, while others were regulated by both of these transcription factors. Several of these regulated genes encode we demonstrate how the X-linked RHOX gene cluster may function in normal human spermatogenesis and we provide evidence that it is impaired in human male fertility.

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“…However, it has been proposed that the closely related Rhox6 gene product could provide functional compensation, as it shares sequence similarity and expression pattern (MacLean and Wilkinson 2010). Rhox5 and Rhox8 are both expressed selectively in Sertoli cells, and their ablation resulted in male subfertility (Maclean, et al 2005, Welborn, et al 2015). It is likely that RHOX proteins may have overlapping functional roles, which would explain why the reproductive defects reported to-date are relatively minor.…”

Section: Discussionmentioning

confidence: 99%

“…A few of the Rhox genes have been targeted in mice by knockout (KO) or RNAi (KD) approaches to determine their roles in fertility. Inactivation of the Sertoli-expressed Rhox5 (by gene KO) and Rhox8 (by siRNA KD) resulted in male subfertility, with increased germ cell apoptosis, reduced cauda epididymal sperm counts, and impaired sperm motility (Maclean, et al 2005, Welborn, et al 2015). …”

Section: Introductionmentioning

confidence: 99%

Rhox13 is required for a quantitatively normal first wave of spermatogenesis in mice

Busada¹,

Velte²,

Serra³

et al. 2016

Reproduction

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We previously described a novel germ cell-specific X-linked reproductive homeobox gene (Rhox13) that is upregulated at the level of translation in response to retinoic acid (RA) in differentiating spermatogonia and preleptotene spermatocytes. We hypothesize that RHOX13 plays an essential role in male germ cell differentiation, and have tested this by creating a Rhox13 gene knockout (KO) mouse. Rhox13 KO mice are born in expected Mendelian ratios, and adults have slightly reduced testis weights, yet a full complement of spermatogenic cell types. Young KO mice (at ~7–8 weeks of age) have a ≈50% reduction in epididymal sperm counts, but numbers increased to WT levels as the mice reach ~ 17 weeks of age. Histological analysis of testes from juvenile KO mice reveal a number of defects during the first wave of spermatogenesis. These include increased apoptosis, delayed appearance of round spermatids, and disruption of the precise stage-specific association of germ cells within the seminiferous tubules. Breeding studies reveal that both young and aged KO males produce normal-sized litters. Taken together, our results indicate that RHOX13 is not essential for mouse fertility in a controlled laboratory setting, but that it is required for optimal development of differentiating germ cells and progression of the first wave of spermatogenesis.

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Rhox8 Ablation in the Sertoli Cells Using a Tissue-Specific RNAi Approach Results in Impaired Male Fertility in Mice1

Cited by 27 publications

References 45 publications

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

The Homeobox Transcription Factor RHOX10 Drives Mouse Spermatogonial Stem Cell Establishment

The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Rhox13 is required for a quantitatively normal first wave of spermatogenesis in mice

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