• PMID: 26832838
• Gene Name: CUL4B
• Condition: Post-meiotic sperm morphogenesis, Male infertility
• Association: Associated
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: Post-meiotic sperm morphogenesis, Male infertility

Human X-linked Intellectual Disability Factor CUL4B Is Required for Post-meiotic Sperm Development and Male Fertility

Lin CY, Chen CY, Yu CH, Yu IS, Lin SR, Wu JT, Lin YH, Kuo PL, Wu JC, Lin SW.

In this study, we demonstrate that an E3-ubiquitin ligase associated with human X-linked intellectual disability, CUL4B, plays a crucial role in post-meiotic sperm development. Initially, Cul4b(Δ)/Y male mice were found to be sterile and exhibited a progressive loss in germ cells, thereby leading to oligoasthenospermia. Adult Cul4b mutant epididymides also contained very low numbers of mature spermatozoa, and these spermatazoa exhibited pronounced morphological abnormalities. In post-meiotic spermatids, CUL4B was dynamically expressed and mitosis of spermatogonia and meiosis of spermatocytes both appeared unaffected. However, the spermatids exhibited significantly higher levels of apoptosis during spermiogenesis, particularly during the acrosome phase through the cap phase. Comparative proteomic analyses identified a large-scale shift between wild-type and Cul4b mutant testes during early post-meiotic sperm development. Ultrastructural pathology studies further detected aberrant acrosomes in spermatids and nuclear morphology. The protein levels of both canonical and non-canonical histones were also affected in an early spermatid stage in the absence of Cul4b. Thus, X-linked CUL4B appears to play a critical role in acrosomal formation, nuclear condensation, and in regulating histone dynamics during haploid male germ cell differentiation in relation to male fertility in mice. Thus, it is possible that CUL4B-selective substrates are required for post-meiotic sperm morphogenesis. FAU - Lin, Chien-Yu AU - Lin CY AD - Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. FAU - Chen, Chun-Yu AU - Chen CY AD - Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. FAU - Yu, Chih-Hsiang AU - Yu CH AD - Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan. FAU - Yu, I-Shing AU - Yu IS AD - Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan. FAU - Lin, Shu-Rung AU - Lin SR AD - Department of Bioscience Technology, College of Science, Chung-Yuan Christian University, Taoyuan, Taiwan. FAU - Wu, June-Tai AU - Wu JT AD - Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan. FAU - Lin, Ying-Hung AU - Lin YH AD - Graduate Institute of Basic Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan. FAU - Kuo, Pao-Lin AU - Kuo PL AD - Graduate Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan. AD - Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. FAU - Wu, Jui-Ching AU - Wu JC AD - Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.