• PMID: 26846852
• Gene Name: CUL4B
• Condition: Important for Spermatogenesis, Male infertility
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Important for Spermatogenesis, Male infertility

Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis

Yin Y, Liu L, Yang C, Lin C, Veith GM, Wang C, Sutovsky P, Zhou P, Ma L.

CUL4B ubiquitin ligase belongs to the cullin-RING ubiquitin ligase family. Although sharing many sequence and structural similarities, CUL4B plays distinct roles in spermatogenesis from its homologous protein CUL4A. We previously reported that genetic ablation ofCul4ain mice led to male infertility because of aberrant meiotic progression. In the present study, we generated Cul4bgerm cell-specific conditional knock-out (Cul4b(Vasa)),as well asCul4bglobal knock-out (Cul4b(Sox2)) mouse, to investigate its roles in spermatogenesis. Germ cell-specific deletion of Cul4bled to male infertility, despite normal testicular morphology and comparable numbers of spermatozoa. Notably, significantly impaired sperm mobility caused by reduced mitochondrial activity and glycolysis level were observed in the majority of the mutant spermatozoa, manifested by low, if any, sperm ATP production. Furthermore,Cul4b(Vasa)spermatozoa exhibited defective arrangement of axonemal microtubules and flagella outer dense fibers. Our mass spectrometry analysis identified INSL6 as a novel CUL4B substrate in male germ cells, evidenced by its direct polyubiquination and degradation by CUL4B E3 ligase. Nevertheless,Cul4bglobal knock-out males lost their germ cells in an age-dependent manner, implying failure of maintaining the spermatogonial stem cell niche in somatic cells. Taken together, our results show that CUL4B is indispensable to spermatogenesis, and it functions cell autonomously in male germ cells to ensure spermatozoa motility, whereas it functions non-cell-autonomously in somatic cells to maintain spermatogonial stemness. Thus, CUL4B links two distinct spermatogenetic processes to a single E3 ligase, highlighting the significance of ubiquitin modification during spermatogenesis. CI - © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Yin, Yan AU - Yin Y AD - From the Division of Dermatology, Department of Medicine and. FAU - Liu, Liren AU - Liu L AD - the Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, and. FAU - Yang, Chenyi AU - Yang C AD - the Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, and. FAU - Lin, Congxing AU - Lin C AD - From the Division of Dermatology, Department of Medicine and. FAU - Veith, George Michael AU - Veith GM AD - From the Division of Dermatology, Department of Medicine and. FAU - Wang, Caihong AU - Wang C AD - the Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri 63110. FAU - Sutovsky, Peter AU - Sutovsky P AD - the Division of Animal Sciences and the Departments of Obstetrics, Gynecology and Women's Health, University of Missouri, Columbia, Missouri 65211. FAU - Zhou, Pengbo AU - Zhou P AD - the Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, and.