Cdc42 activity in Sertoli cells is essential for maintenance of spermatogenesis

Heinrich, Anna; Bhandary, Bidur; Potter, Sarah; Ratner, Nancy; DeFalco, Tony

doi:10.1016/j.celrep.2021.109885

Cited by 25 publications

(14 citation statements)

References 68 publications

(70 reference statements)

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“…Consistent with these reports, we found that PAFAH1B1 interacts with IQGAP1, and knockdown of Pafah1b1 significantly decreases CDC42 level in murine SCs. Conditional deletion of Cdc42 in Sertoli cells leads to the disrupted Sertoli cell polarity and the perturbed BTB function in adult male mice [60], and inactivation of the CDC42 signaling pathway attenuates the endothelial barrier function in mouse lungs [61]. Our study demonstrates that inhibition of Pafah1b1 results in downregulation of CDC42 and its downstream PAK1, LIMK1, and p-Cofilin.…”

Section: Discussionmentioning

confidence: 58%

Sertoli cell survival and barrier function are regulated by miR-181c/d-Pafah1b1 axis during mammalian spermatogenesis

Feng

Chen

Wang

et al. 2022

Cell. Mol. Life Sci.

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Sertoli cells contribute to the formation of the blood-testis barrier (BTB), which is necessary for normal spermatogenesis. Recently, microRNAs (miRNAs) have emerged as posttranscriptional regulatory elements in BTB function during spermatogenesis. Our previous study has shown that miR-181c or miR-181d (miR-181c/d) is highly expressed in testes from boars at 60 days old compared with at 180 days old. Herein, we found that overexpression of miR-181c/d via miR-181c/d mimics in murine Sertoli cells (SCs) or through injecting miR-181c/d-overexpressing lentivirus in murine testes perturbs BTB function by altering BTB-associated protein distribution at the Sertoli cell–cell interface and F-actin organization, but this in vivo perturbation disappears approximately 6 weeks after the final treatment. We also found that miR-181c/d represses Sertoli cell proliferation and promotes its apoptosis. Moreover, miR-181c/d regulates Sertoli cell survival and barrier function by targeting platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (Pafah1b1) gene. Furthermore, miR-181c/d suppresses PAFAH1B1 expression, reduces the complex of PAFAH1B1 with IQ motif-containing GTPase activating protein 1, and inhibits CDC42/PAK1/LIMK1/Cofilin pathway which is required for F-actin stabilization. In total, our results reveal the regulatory axis of miR-181c/d-Pafah1b1 in cell survival and barrier function of Sertoli cells and provide additional insights into miRNA functions in mammalian spermatogenesis.

show abstract

Section: Discussionmentioning

confidence: 58%

Sertoli cell survival and barrier function are regulated by miR-181c/d-Pafah1b1 axis during mammalian spermatogenesis

Feng

Chen

Wang

et al. 2022

Cell. Mol. Life Sci.

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show abstract

“…Consistent with these reports, we found that PAFAH1B1 interacts with IQGAP1, and knockdown of Pafah1b1 signi cantly decreases CDC42 level in murine SCs. Conditional deletion of Cdc42 in Sertoli cells leads to the disrupted Sertoli cell polarity and the perturbed BTB function in adult male mice [59], and inactivation of the CDC42 signaling pathway attenuates the endothelial barrier function in mouse lungs [60]. Our study demonstrates that inhibition of Pafah1b1 results in downregulation of CDC42 and its downstream PAK1, LIMK1, and p-Co lin.…”

Section: Discussionmentioning

confidence: 70%

Sertoli cell survival and barrier function are regulated by miR-181c/d-Pafah1b1 axis during mammalian spermatogenesis

Feng

Chen

Wang

et al. 2022

Preprint

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Sertoli cells contribute to the formation of the blood-testis barrier (BTB), which is necessary for normal spermatogenesis. Recently, microRNAs (miRNAs) have emerged as posttranscriptional regulatory elements in BTB function during spermatogenesis. Our previous study has shown that miR-181c or miR-181d (miR-181c/d) is highly expressed in testes from boars at 60 days old compared with at 180 days old. Herein, we found that overexpression of miR-181c/d via miR-181c/d mimics in murine Sertoli cells (SCs) or miR-181c/d-overexpressing lentivirus in murine testes perturbs BTB function by altering BTB-associated protein distribution at the Sertoli cell-cell interface and F-actin organization, but this in vivo perturbation disappears approximately six weeks after the final treatment. We also found that miR-181c/d represses Sertoli cell proliferation and promotes its apoptosis. Moreover, miR-181c/d regulates Sertoli cell survival and barrier function by targeting platelet-activating factor acetylhydrolase 1b regulatory subunit 1 (Pafah1b1) gene. Furthermore, miR-181c/d suppresses PAFAH1B1 expression, reduces the complex of PAFAH1B1 with IQ motif-containing GTPase activating protein 1, and inhibits CDC42/PAK1/LIMK1/Cofilin pathway which is required for F-actin stabilization. In total, our results reveal the regulatory axis of miR-181c/d-Pafah1b1 in cell survival and barrier function of Sertoli cells, and provide additional insights into miRNA functions on the spermatogenesis process in mammals.

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“…Although Sertoli cell polarity is critical for effective spermatogenesis, it is unclear when and how these cells become polarized [ 36 ]. Rho GTPase signaling has been linked to cell polarity and other cellular processes (e.g., cell cycle, cell migration, cytoskeletal structure) in a variety of biological situations [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Whole Exome Sequencing and In Silico Analysis of Human Sertoli in Patients with Non-Obstructive Azoospermia

Azizi

Karoii

Skutella

2022

IJMS

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Non-obstructive azoospermia (NOA) is a serious cause of male infertility. The Sertoli cell responds to androgens and takes on roles supporting spermatogenesis, which may cause infertility. This work aims to enhance the genetic diagnosis of NOA via the discovery of new and hub genes implicated in human NOA and to better assess the odds of successful sperm extraction according to the individual’s genotype. Whole exome sequencing (WES) was done on three NOA patients to find key genes involved in NOA. We evaluated genome-wide transcripts (about 50,000 transcripts) by microarray between the Sertoli of non-obstructive azoospermia and normal cells. The microarray analysis of three human cases with different non-obstructive azoospermia revealed that 32 genes were upregulated, and the expressions of 113 genes were downregulated versus the normal case. For this purpose, Enrich Shiny GO, STRING, and Cytoscape online evaluations were applied to predict the functional and molecular interactions of proteins and then recognize the master pathways. The functional enrichment analysis demonstrated that the biological process (BP) terms “inositol lipid-mediated signaling”, “positive regulation of transcription by RNA polymerase II”, and “positive regulation of DNA-templated transcription” significantly changed in upregulated differentially expressed genes (DEGs). The BP investigation of downregulated DEGs highlighted “mitotic cytokinesis”, “regulation of protein-containing complex assembly”, “cytoskeleton-dependent cytokinesis”, and the “peptide metabolic process”. Overrepresented molecular function (MF) terms in upregulated DEGs included “ubiquitin-specific protease binding”, “protease binding”, “phosphatidylinositol trisphosphate phosphatase activity”, and “clathrin light chain binding”. Interestingly, the MF analysis of the downregulated DEGs revealed overexpression in “ATPase inhibitor activity”, “glutathione transferase activity”, and “ATPase regulator activity”. Our findings suggest that these genes and their interacting hub proteins could help determine the pathophysiologies of germ cell abnormalities and infertility.

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Cdc42 activity in Sertoli cells is essential for maintenance of spermatogenesis

Cited by 25 publications

References 68 publications

Sertoli cell survival and barrier function are regulated by miR-181c/d-Pafah1b1 axis during mammalian spermatogenesis

Sertoli cell survival and barrier function are regulated by miR-181c/d-Pafah1b1 axis during mammalian spermatogenesis

Sertoli cell survival and barrier function are regulated by miR-181c/d-Pafah1b1 axis during mammalian spermatogenesis

Whole Exome Sequencing and In Silico Analysis of Human Sertoli in Patients with Non-Obstructive Azoospermia

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