Authors gratefully acknowledge the Translational Study Unit in the Institute of Pathology for great technical assistance, as well as the help of your Tissue Bank Bern at the Institute of Pathology, University of Bern, in acquiring patient tissue, as well as the Cancer registry Bern for support acquiring survival data. Conflicts of Interest: The authors declare no conflict of interest.
cellsArticleCullin4 E3 Ubiquitin Ligases Regulate Male Gonocyte Migration, Proliferation and Blood-Testis 1-Dodecanol-d25 Cancer Barrier HomeostasisYan Yin 1 , Liming Zhu 1 , Qiufang Li 1 , Pengbo Zhou two and Liang Ma 1, Division of Medicine, Division of Dermatology, Washington University College of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; [email protected] (Y.Y.); [email protected] (L.Z.); [email protected] (Q.L.) Division of Pathology and Laboratory Medicine, The Joan and Stanford I. Weill Medical College of Cornell University, New York, NY 10021, USA; [email protected] Correspondence: [email protected]; Fax: +1-314-454-Citation: Yin, Y.; Zhu, L.; Li, Q.; Zhou, P.; Ma, L. Cullin4 E3 Ubiquitin Ligases Regulate Male Gonocyte Migration, Proliferation and Blood-Testis Barrier Homeostasis. Cells 2021, 10, 2732. https://doi.org/ 10.3390/cells10102732 Academic Editors: Peter Sutovsky and Michal ZigoAbstract: Ubiquitination, an important posttranslational modification, plays basic roles throughout mammalian spermatogenesis. We previously reported the requirement of two Cullin four ubiquitin ligase family members genes, Cullin 4a (Cul4a) and Cullin 4b (Cul4b), in murine spermatogenesis. Each genes are essential for male CMP-Sialic acid sodium salt supplier fertility despite their distinct functions in diverse cell populations. Cul4a is required in key spermatocytes to market meiosis while Cul4b is needed in secondary spermatocytes for spermiogenesis. Because the two genes encode proteins that are hugely homologous and have overlapping expression in embryonic germ cells, they might compensate for every other throughout germ cell improvement. Inside the present study, we straight address the prospective functional redundancy of these two proteins by deleting both Cul4 genes, specifically, within the germ cell lineage through embryonic improvement, working with the germ-cell precise Vasa-Cre line. Conditional double-knockout (dKO) males showed delayed homing and impaired proliferation of gonocytes, along with a total loss of germ cells just before the end in the very first wave of spermatogenesis. The dKO male germ cell phenotype is substantially additional extreme than these observed in either single KO mutant, demonstrating the functional redundancy between the two CUL4 proteins. The dKO mutant also exhibited atypical tight junction structures, suggesting the possible involvement of CUL4 proteins in spermatogonial stem cell (SSC) niche formation and blood estis-barrier (BTB) maintenance. We also show that deleting Cul4b in both germ and Sertoli cells is adequate to recapitulate portion of this phenotype, causing spermatogenesis defects and drastically reduced quantity of mature sperms, accompanied by defective tight junctions inside the mutant testes. These results indicate the involvement of CUL4B in keeping BTB integrity. Search phrases: ubiquitination; Cullin4; spermatogenesis; blood-testis barrierReceived: two September 2021 Accepted: 5 October 2021 Published: 13 OctoberPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.1. Introduction Male infertility, a major challenge in reproduction, affects a.
