DDB1- and CUL4-associated factor 8 plays a critical role in spermatogenesis

Abstract

Cullin-RING E3 ubiquitin ligase (CRL)-4 is a member of the large CRL family in eukaryotes. It plays important roles in a wide range of cellular processes, organismal development, and physiological and pathological conditions. DDB1- and CUL4-associated factor 8 (DCAF8) is a WD40 repeat-containing protein, which serves as a substrate receptor for CRL4. The physiological role of DCAF8 is unknown. In this study, we constructed Dcaf8 knockout mice. Homozygous mice were viable with no noticeable abnormalities. However, the fertility of Dcaf8-deficient male mice was markedly impaired, consistent with the high expression of DCAF8 in adult mouse testis. Sperm movement characteristics, including progressive motility, path velocity, progressive velocity, and track speed, were significantly lower in Dcaf8 knockout mice than in wild-type (WT) mice. However, the total motility was similar between WT and Dcaf8 knockout sperm. More than 40% of spermatids in Dcaf8 knockout mice showed pronounced morphological abnormalities with typical bent head malformation. The acrosome and nucleus of Dcaf8 knockout sperm looked similar to those of WT sperm. In vitro tests showed that the fertilization rate of Dcaf8 knockout mice was significantly reduced. The results demonstrated that DCAF8 plays a critical role in spermatogenesis, and DCAF8 is a key component of CRL4 function in the reproductive system.

Keywords

Dcaf8 / male infertility / spermatogenesis

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Acknowledgements

This work was supported by the Key Program of Natural Science Foundation of China (Nos. 8153006 and 81870112 to Ruibao Ren, No. 81970134 to Ping Liu), Shanghai Science and Technology Development Funds (No. 18ZR1423600 to Ruibao Ren), Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research (No. 2019CXJQ01 to Ruibao Ren), the Samuel Waxman Cancer Research Foundation and Innovative Research Team of High-level Local Universities in Shanghai (to Ruibao Ren).

Compliance with ethics guidelines

Xiuli Zhang, Zhizhou Xia, Xingyu Lv, Donghe Li, Mingzhu Liu, Ruihong Zhang, Tong Ji, Ping Liu, and Ruibao Ren declare that they have no conflicts of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0851-8 and is accessible for authorized users.

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