hnRNPU in Sertoli cells cooperates with WT1 and is essential for testicular development by modulating transcriptional factors <i>Sox8/9</i>

Wen, Yujiao; Ma, Xixiang; Wang, Xiaoli; Wang, Fengli; Dong, Juan; Wu, Yanqing; Lv, Chunyu; Liu, Kuan; Zhang, Yan; Zhang, Zhibing; Yuan, Shuiqiao

doi:10.7150/thno.66819

Cited by 25 publications

(25 citation statements)

References 63 publications

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“…Second, our previous study con rmed that hnRNPU binds to Sox8/9 as a co-transcription factor to regulate gene transcription (Wen et al, 2021), whereas this study revealed that hnRNPU binds to RNA to regulate RNA splicing at a post-transcriptional level. Third, the current study demonstrated that hnRNPU could regulate ProSG to SSC progression by affecting the alternative splicing of genes related to cell cycles, such as Vrk1, Slx4, Dazl, Apbb2, and Zfp707 (Fig.…”

Section: Discussionmentioning

confidence: 61%

“…hnRNPU expression traversing germ cell development and is highly expressed in spermatogonia Since we previously identi ed that hnRNPU was highly expressed in mouse Sertoli cells and male germ cells (Wen et al, 2021), in the current report, we assessed the cellular localization of hnRNPU in adult mouse male germ cells by IMF (Immuno uorescence) analyses of hnRNPU colocalization with γ-H2AX and SYCP3 to explore the role of hnRNPU in male germ cell development. The result showed that hnRNPU was highly expressed in the nucleus of spermatogonia, pachytene spermatocytes, and round spermatids in the seminiferous tubules (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the role of hnRNPU during spermatogenesis, especially in early male germ cell development, we adopt a Cre-LoxPmediated gene recombination strategy and mated Vasa-Cre mouse line with the previously described Hnrnpu lox/lox mouse line (Wen et al, 2021). After recombination, the exon 4-14 anked by loxP sites of Hnrnpu was deleted in germ cells from E15.5 (Figure S2A).…”

Section: Ablation Of Hnrnpu In Prospermatogonia Leads To Sertoli Cell...mentioning

confidence: 99%

“…In addition to the classical role of hnRNPs in binding to nascent mRNA, the functions of hnRNPs in various biological processes have been successively con rmed, such as DNA transcription, pre-mRNA alternative splicing, mRNA stability, and protein translation (van Eekelen et al, 1981). Notably, our previous study characterized one of hnRNP family members, hnRNPU, as a co-transcription factor that interacts with WT1 and SOX9 and regulates the transcription of Sox8/9 in mouse Sertoli cells (Wen et al, 2021). However, the role of hnRNPU in male germ cell development remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Sertoli cell-only phenotype and scRNA-seq reveal hnRNPU as a regulator required for spermatogonial stem cell pool establishment in mice

Yuan

Wen

Zhou

et al. 2022

Preprint

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The continuous regeneration of spermatogonial stem cells (SSCs) underpins spermatogenesis and lifelong male fertility; however, little is known about the developmental origins of the SSC pool. Here, we document that heterogeneous nuclear ribonucleoprotein U (hnRNPU) is essential for establishing the SSC pool. In male mice, conditional loss of hnRNPU in prospermatogonia (ProSG) arrests spermatogenesis and results in sterility, characterized by complete loss of germ cells around postnatal day 10, which resembles the Sertoli cell-only phenotype in humans. hnRNPU-deficient ProSG fails to differentiate and migrate to the basement membrane to establish SSC pool in infancy. Moreover, we find that the deletion of hnRNPU leads to the accumulation of ProSG and the reduction of undifferentiated spermatogonia and further disrupts the process of T1-ProSG to T2-ProSG transition. hnRNPU-deficiency in ProSG deregulates the expression of spermatogenic-related genes and destroys the alternative splicing of genes related to cell cycles, and single-cell transcriptional analyses reveal germ cells are in a mitotically quiescent state and lost their unique identity upon hnRNPU deletion. We further show that hnRNPU could interact with DDX5, SRSF3, and TRIM28 proteins and bind to Vrk1, Slx4, and Dazl transcripts with identified to be suffered aberrant alternative splicing in hnRNPU-deficient testes. These observations give important insights into SSC pool establishment and may have translational implications for male fertility.

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Section: Discussionmentioning

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Ablation Of Hnrnpu In Prospermatogonia Leads To Sertoli Cell...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Sertoli cell-only phenotype and scRNA-seq reveal hnRNPU as a regulator required for spermatogonial stem cell pool establishment in mice

Yuan

Wen

Zhou

et al. 2022

Preprint

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“…The results of this study showed that after 5 weeks of ZEA (30 μg/kg) treatment, the ZEA treatment group significantly reduced the sperm motility, concentration, and sperm motility parameters of mice. SOX9 is expressed only in the Sertoli cells of the testis and plays an important role in testicular development [ 31 , 32 ]. Spermatogenesis is regulated by SYCP3 and DDX4 .…”

Section: Discussionmentioning

confidence: 99%

Effect of Zearalenone-Induced Ferroptosis on Mice Spermatogenesis

Zhu

Cui

Ding

et al. 2022

Animals

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Male reproductive health is critically worsening around the world. It has been reported that the mycotoxin ZEA causes reproductive toxicity to domestic animals and affects spermatogenesis, thereby inhibiting male reproductive function. Ferroptosis is a newly identified type of programmed cell death that is different from apoptosis and it depends on iron accumulation and lipid peroxidation. Whether ferroptosis is linked to ZEA’s detrimental effect on spermatogenesis needs to be further explored. This study clarifies ferroptosis’s involvement in ZEA-induced damage on spermatogenesis. The reproductive injury model used in this study was induced by gavaging male mice in the ZEA treatment group with 30 μg/kg of ZEA for five weeks. Results show that ZEA treatment reduced mouse sperm motility and concentration, destroyed the structure of the seminiferous tubules of the testis, damaged the antioxidant defense system, and blocked spermatogenesis. Ferrostatin-1 (Fer-1) inhibition of ferroptosis partially alleviated ZEA-induced oligozoospermia in mice. In addition, ZEA treatment was found to activate a signaling pathway associated with ferroptosis in mouse testis. ZEA also downregulated the expression of Nrf2, SLC7A11, and GPX4, and decreased the protein expression of SLC7A11 and GPX4, resulting in the accumulation of lipid peroxides and an increase in the level of 4-HNE protein in the testis. Importantly, these changes were accompanied by an increase in the relative contents of Fe2+ and Fe3+. Iron accumulation and lipid peroxidation are the causes of ferroptosis in spermatogenic cells, leading to a decrease in sperm motility and concentration. While the administration of Fer-1 at 0.5 and 1 mg/kg also increased the expression of SLC7A11 and GPX4 proteins by upregulating Nrf2 expression, reducing iron accumulation, and reversing ZEA-induced ferroptosis, Fer-1 at 1.5 mg/kg had the best repairing effect for all parameters. In conclusion, ZEA-induced ferroptosis may be mediated by a notable reduction in Nrf2, SLC7A11 and GPX4 expression levels. Overall, ferroptosis is a novel therapeutic target for mitigating ZEA-induced reproductive toxicity.

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Puerarin improves busulfan-induced disruption of spermatogenesis by inhibiting MAPK pathways

Li¹,

Zhong²,

Xia³

et al. 2023

Biomedicine & Pharmacotherapy

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hnRNPU in Sertoli cells cooperates with WT1 and is essential for testicular development by modulating transcriptional factors Sox8/9

Cited by 25 publications

References 63 publications

Sertoli cell-only phenotype and scRNA-seq reveal hnRNPU as a regulator required for spermatogonial stem cell pool establishment in mice

Sertoli cell-only phenotype and scRNA-seq reveal hnRNPU as a regulator required for spermatogonial stem cell pool establishment in mice

Effect of Zearalenone-Induced Ferroptosis on Mice Spermatogenesis

Puerarin improves busulfan-induced disruption of spermatogenesis by inhibiting MAPK pathways

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