Coiled-coil domain-containing 38 is required for acrosome biogenesis and fibrous sheath assembly in mice

Yaling Wang; Xueying Huang; Guoying Sun; Jingwen Chen; Bangguo Wu; Jiahui Luo; Shuyan Tang; Peng Dai; Feng Zhang; Jinsong Li; Lingbo Wang

doi:10.1016/j.jgg.2023.09.002

Coiled-coil domain-containing 38 is required for acrosome biogenesis and fibrous sheath assembly in mice

J Genet Genomics. 2024 Apr;51(4):407-418. doi: 10.1016/j.jgg.2023.09.002. Epub 2023 Sep 13.

Authors

Yaling Wang¹, Xueying Huang², Guoying Sun³, Jingwen Chen¹, Bangguo Wu¹, Jiahui Luo³, Shuyan Tang⁴, Peng Dai², Feng Zhang¹, Jinsong Li⁵, Lingbo Wang⁶

Affiliations

¹ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China; Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
² Shanghai Key Laboratory of Maternal and Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
³ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
⁴ Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China.
⁵ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China.
⁶ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China; Institute of Reproduction and Development, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China. Electronic address: wanglingbo@fudan.edu.cn.

PMID: 37709195
DOI: 10.1016/j.jgg.2023.09.002

Abstract

During spermiogenesis, haploid spermatids undergo dramatic morphological changes to form slender sperm flagella and cap-like acrosomes, which are required for successful fertilization. Severe deformities in flagella cause a male infertility syndrome, multiple morphological abnormalities of the flagella (MMAF), while acrosomal hypoplasia in some cases leads to sub-optimal embryonic developmental potential. However, evidence regarding the occurrence of acrosomal hypoplasia in MMAF is limited. Here, we report the generation of base-edited mice knocked out for coiled-coil domain-containing 38 (Ccdc38) via inducing a nonsense mutation and find that the males are infertile. The Ccdc38-KO sperm display acrosomal hypoplasia and typical MMAF phenotypes. We find that the acrosomal membrane is loosely anchored to the nucleus and fibrous sheaths are disorganized in Ccdc38-KO sperm. Further analyses reveal that Ccdc38 knockout causes a decreased level of TEKT3, a protein associated with acrosome biogenesis, in testes and an aberrant distribution of TEKT3 in sperm. We finally show that intracytoplasmic sperm injection overcomes Ccdc38-related infertility. Our study thus reveals a previously unknown role for CCDC38 in acrosome biogenesis and provides additional evidence for the occurrence of acrosomal hypoplasia in MMAF.

Keywords: Acrosomal hypoplasia; Asthenoteratozoospermia; Disease modeling; Infertility; Multiple morphological abnormalities of the flagella (MMAF); Sperm motility.

MeSH terms

Acrosome*
Animals
Male
Mice
Mutation
Semen* / metabolism
Sperm Tail / metabolism
Spermatogenesis / genetics
Spermatozoa