RNA kinase CLP1/Cbc regulates meiosis initiation in spermatogenesis

Abstract

CLP1, TSEN complex, and VCP are evolutionarily conserved proteins whose mutations are associated with neurodegenerative diseases. In this study, we have found that they are also involved in germline differentiation. To optimize both quantity and quality in gametes production, germ cells expand themselves through limited mitotic cycles prior to meiosis. Stemming from our previous findings on the correlation between mRNA 3′-processing and meiosis entry, here we identify that the RNA kinase Cbc, the Drosophila member of the highly conserved CLP1 family, is a component of the program regulating the transition from mitosis to meiosis. Using genetic manipulations in Drosophila testis, we demonstrate that nuclear Cbc is required to promote meiosis entry. Combining biochemical and genetic methods, we reveal that Cbc physically and/or genetically intersects with Tsen54 and TER94 (VCP ortholog) in this process. The C-terminal half of Tsen54 is both necessary and sufficient for its binding with Cbc. Further, we illustrate the functional conservation between Cbc and mammalian CLP1 in the assays of subcellular localization and Drosophila fertility. As CLP1, TSEN complex, and VCP have also been identified in neurodegenerations of animal models, a mechanism involving these factors seems to be shared in gametogenesis and neurogenesis.

VCP acts downstream of tTAFs to downregulate mono-ubiquitinated H2A and promote spermatocyte differentiation inDrosophila

“…Although previous studies have demonstrated that VCP influences germ-cell health and development (León and McKearin, 1999; Sasagawa, et al, 2012; Sasagawa, et al, 2009; Sasagawa, et al, 2007; Wu, et al, 2021), fundamental questions remain regarding how VCP functions and is regulated in this biological context, particularly in the male germline. In this study, we found that VCP translocates from the cytosol to the nucleus at the mitotic-meiotic transition, and downregulates H2Aub to promote changes in gene expression needed for subsequent stages of spermatogenesis (Fig.…”

“…In oocytes of the nematode Caenorhabditis elegans , CDC-48/VCP appears particularly significant during meiotic divisions, when it regulates chromosome condensation and segregation (Mouysset, et al, 2008; Sasagawa, et al, 2012; Sasagawa, et al, 2009; Sasagawa, et al, 2007). While there are indications that VCP may likewise perform regulatory roles during sperm development (Wu, et al, 2021), it is unclear at what stage VCP function may be most critical. Stage-specific transcriptomic data from Drosophila testes suggest that ter94/VCP is strongly expressed in meiotic-stage spermatocytes (Shi, et al, 2020).…”

“…While there are indications that VCP may likewise perform regulatory roles during sperm development (Wu, et al, 2021), it is unclear at what stage VCP function may be most critical. Stage-specific transcriptomic data from Drosophila testes suggest that ter94/VCP is strongly expressed in meiotic-stage spermatocytes (Shi, et al, 2020).…”

A Developmental Mechanism to Regulate Alternative Polyadenylation in an Adult Stem Cell Lineage

“…To further increase KD penetrance, we used a Gal4 driver that also expressed UAS > dicer2. Fly lines used in this study: W1118 (BL #3605), Bam Gal4 (Chen and McKearin 2003), CPSF6:GFP (VDRC #318105), HA:Cbc (N-terminal CRISPR tag, kindly gimed from the Wang lab, (Wu et al 2021)), PCF11-RNAi_1…”

Genomic analysis of the rhesus macaque (Macaca mulatta) and the cynomolgus macaque (Macaca fascicularis) uncover polygenic signatures of reinforcement speciation

“…The homolog of CLP1 (cbc) in Drosophila has been demonstrated to be necessary for spermatogenesis and function of this gene can be recovered in KO flies using human and mouse orthologs, suggesting a similar function (Wu et al, 2021).…”