Abstract
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, Cul4bΔ/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.
Highlights
Mammalian spermatogenesis is a complex and dynamic process that involves cell division and differentiation in the seminiferous tubules of the testes
We present evidence that the dynamic expression of mammalian CUL4B in post-meiotic spermatids is a key factor in regulating the early steps of post-meiotic sperm development
CUL4B appears to be crucial for regulating a genome-wide coordination of the transformation that occurs during spermiogenesis
Summary
Mammalian spermatogenesis is a complex and dynamic process that involves cell division and differentiation in the seminiferous tubules of the testes. Gene ontology analyses have further revealed that the expression of genes involved in protein turnover are elevated Together, these results indicate that spermiogenesis is highly dynamic and it requires controlled regulation of protein degradation[9]. E3 ligase proteins in the ubiquitin-proteasome system (UPS) and selectively recognize proteins targeted for ubiquitination These proteins are hypothesized to play a key role in maintaining functional spermatogenesis. CUL4B serves as scaffolding proteins for the E3 ubiquitin ligase Both CUL4A and CUL4B use the same substrate adaptor, DDB1, to target similar substrates for cellular functions, such as regulation of chromosome function[18,19], maintenance of genome integrity[20] and cell cycle progression[21]. The in-vivo significance of the regulation of these interactions by CUL4B has not been intensively studied
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