Essential Regulation of YAP1 in Fate Determinations of Spermatogonial Stem Cells and Male Fertility by Interacting with RAD21 and Targeting NEDD4 in Humans and Mice

Overview

Journal Research (Wash D C)

Specialty Biology

Date 2024 Dec 11

PMID 39659446

Authors

Chunyun Li

Wei Chen

Yinghong Cui

Dong Zhang

Qingqing Yuan

Xing Yu

Zuping He

Affiliations

Soon will be listed here.

Abstract

Spermatogenesis is a sophisticated biological process by which spermatogonial stem cells (SSCs) undergo self-renewal and differentiation into spermatozoa. Molecular mechanisms underlying fate determinations of human SSCs by key genes and signaling pathways remain elusive. Here, we report for the first time that Yes1-associated transcriptional regulator (YAP1) is required for fate determinations of SSCs and male fertility by interacting with RAD21 and targeting NEDD4 in humans and mice. YAP1 was mainly located at cell nuclei of human SSCs. YAP1 silencing resulted in the decreases in proliferation and DNA synthesis as well as an enhancement in apoptosis of human SSCs both in vivo and in vitro. RNA sequencing and real-time polymerase chain reaction assays identified NEDD4 as a target of YAP1, and NEDD4 knockdown inhibited the proliferation of human SSCs and increased their apoptosis. Furthermore, YAP1 interacted with RAD21 to regulate NEDD4 transcription in human SSCs. Importantly, YAP1 abnormalities were found to be associated with non-obstructive azoospermia (NOA) as manifested as lower expression level of YAP1 in testicular tissues of NOA patients and single-nucleotide variants (SNVs) in 777 NOA patients. Finally, germline conditional knockout (cKO) mice assumed mitotic arrest, low sperm count, and motility. Collectively, these results highlight a critical role of YAP1 in determining the fate determinations of human SSCs and male infertility through the YAP1/RAD21/NEDD4 pathway. This study provides new insights into the genetic regulatory mechanisms underlying human spermatogenesis and the pathogenesis of NOA, and it offers new targets for gene therapy of male infertility.

References

Liu C, Tu C, Wang L, Wu H, Houston B, Mastrorosa F . Deleterious variants in X-linked CFAP47 induce asthenoteratozoospermia and primary male infertility. Am J Hum Genet. 2021; 108(2):309-323. PMC: 7895902. DOI: 10.1016/j.ajhg.2021.01.002. View

LeBlanc L, Ramirez N, Kim J . Context-dependent roles of YAP/TAZ in stem cell fates and cancer. Cell Mol Life Sci. 2021; 78(9):4201-4219. PMC: 8164607. DOI: 10.1007/s00018-021-03781-2. View

Wang F, Wang L, Gan S, Feng S, Ouyang S, Wang X . SERBP1 Promotes Stress Granule Clearance by Regulating 26S Proteasome Activity and G3BP1 Ubiquitination and Protects Male Germ Cells from Thermostimuli Damage. Research (Wash D C). 2023; 6:0091. PMC: 10202183. DOI: 10.34133/research.0091. View

Zhang Q, Chen H, Xie C, Qiu G . Potential role for the germ cell-specific Rad21 in early meiosis of oocyte and spermatocyte in the Chinese mitten crab Eriocheir sinensis. Gene. 2023; 862:147262. DOI: 10.1016/j.gene.2023.147262. View

Kim J, Park R, Lee J, Shin J, Nickas J, Kim S . Yap is essential for retinal progenitor cell cycle progression and RPE cell fate acquisition in the developing mouse eye. Dev Biol. 2016; 419(2):336-347. PMC: 5125893. DOI: 10.1016/j.ydbio.2016.09.001. View

Du L, Chen W, Cheng Z, Wu S, He J, Han L . Novel Gene Regulation in Normal and Abnormal Spermatogenesis. Cells. 2021; 10(3). PMC: 8002376. DOI: 10.3390/cells10030666. View

Codino A, Turowski T, van de Lagemaat L, Ivanova I, Tavosanis A, Much C . NANOS2 is a sequence-specific mRNA-binding protein that promotes transcript degradation in spermatogonial stem cells. iScience. 2021; 24(7):102762. PMC: 8271163. DOI: 10.1016/j.isci.2021.102762. View

Chen X, Li Y, Luo J, Hou N . Molecular Mechanism of Hippo-YAP1/TAZ Pathway in Heart Development, Disease, and Regeneration. Front Physiol. 2020; 11:389. PMC: 7191303. DOI: 10.3389/fphys.2020.00389. View

Onn I, Heidinger-Pauli J, Guacci V, Unal E, Koshland D . Sister chromatid cohesion: a simple concept with a complex reality. Annu Rev Cell Dev Biol. 2008; 24:105-29. DOI: 10.1146/annurev.cellbio.24.110707.175350. View

10.

Meng C, Tian G, Xu C, Li X, Zhang Y, Wang Y . Hippo kinases MST1 and MST2 control the differentiation of the epididymal initial segment via the MEK-ERK pathway. Cell Death Differ. 2020; 27(10):2797-2809. PMC: 7492226. DOI: 10.1038/s41418-020-0544-x. View

11.

Wang Z, Cui M, Qu Y, He R, Wu W, Lin H . Hypoxia Protects Rat Bone Marrow Mesenchymal Stem Cells Against Compression-Induced Apoptosis in the Degenerative Disc Microenvironment Through Activation of the HIF-1α/YAP Signaling Pathway. Stem Cells Dev. 2020; 29(20):1309-1319. DOI: 10.1089/scd.2020.0061. View

12.

Kaneshige A, Kaji T, Zhang L, Saito H, Nakamura A, Kurosawa T . Relayed signaling between mesenchymal progenitors and muscle stem cells ensures adaptive stem cell response to increased mechanical load. Cell Stem Cell. 2021; 29(2):265-280.e6. DOI: 10.1016/j.stem.2021.11.003. View

13.

Pan D . The hippo signaling pathway in development and cancer. Dev Cell. 2010; 19(4):491-505. PMC: 3124840. DOI: 10.1016/j.devcel.2010.09.011. View

14.

Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S . Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A. 2013; 110(43):17474-9. PMC: 3808580. DOI: 10.1073/pnas.1312830110. View

15.

Kagey M, Newman J, Bilodeau S, Zhan Y, Orlando D, van Berkum N . Mediator and cohesin connect gene expression and chromatin architecture. Nature. 2010; 467(7314):430-5. PMC: 2953795. DOI: 10.1038/nature09380. View

16.

Xu H, Beasley M, Warren W, van der Horst G, McKay M . Absence of mouse REC8 cohesin promotes synapsis of sister chromatids in meiosis. Dev Cell. 2005; 8(6):949-61. DOI: 10.1016/j.devcel.2005.03.018. View

17.

Sha Q, Zhu Y, Li S, Jiang Y, Chen L, Sun X . Characterization of zygotic genome activation-dependent maternal mRNA clearance in mouse. Nucleic Acids Res. 2019; 48(2):879-894. PMC: 6954448. DOI: 10.1093/nar/gkz1111. View

18.

Gao J, Xu Z, Song W, Huang J, Liu W, He Z . USP11 regulates proliferation and apoptosis of human spermatogonial stem cells via HOXC5-mediated canonical WNT/β-catenin signaling pathway. Cell Mol Life Sci. 2024; 81(1):211. PMC: 11082041. DOI: 10.1007/s00018-024-05248-6. View

19.

Oud M, Volozonoka L, Smits R, Vissers L, Ramos L, Veltman J . A systematic review and standardized clinical validity assessment of male infertility genes. Hum Reprod. 2019; 34(5):932-941. PMC: 6505449. DOI: 10.1093/humrep/dez022. View

20.

Tsoi M, Morin M, Rico C, Johnson R, Paquet M, Gevry N . and are required for ovarian granulosa cell fate maintenance. FASEB J. 2019; 33(10):10819-10832. PMC: 6766663. DOI: 10.1096/fj.201900609R. View