Knockout of serine-rich single-pass membrane protein 1 (Ssmem1) causes globozoospermia and sterility in male mice†

Author:

Nozawa Kaori12,Zhang Qian3,Miyata Haruhiko3,Devlin Darius J124,Yu Zhifeng12,Oura Seiya35,Koyano Takayuki6,Matsuyama Makoto6,Ikawa Masahito3578,Matzuk Martin M12

Affiliation:

1. Center for Drug Discovery, Baylor College of Medicine, Houston, TX

2. Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX

3. Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

4. Interdepartmental Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX

5. Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan

6. Division of Molecular Genetics, Shigei Medical Research Institute, Okayama, Japan

7. Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

8. The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Abstract

Abstract Globozoospermia (sperm with an abnormally round head shape) and asthenozoospermia (defective sperm motility) are known causes of male infertility in human patients. Despite many studies, the molecular details of the globozoospermia etiology are still poorly understood. Serine-rich single-pass membrane protein 1 (Ssmem1) is a conserved testis-specific gene in mammals. In this study, we generated Ssmem1 knockout (KO) mice using the CRISPR/Cas9 system, demonstrated that Ssmem1 is essential for male fertility in mice, and found that SSMEM1 protein is expressed during spermatogenesis but not in mature sperm. The sterility of the Ssmem1 KO (null) mice is associated with globozoospermia and loss of sperm motility. To decipher the mechanism causing the phenotype, we analyzed testes with transmission electron microscopy and discovered that Ssmem1-disrupted spermatids have abnormal localization of Golgi at steps eight and nine of spermatid development. Immunofluorescence analysis with anti-Golgin-97 to label the trans-Golgi network, also showed delayed movement of the Golgi to the spermatid posterior region, which causes failure of sperm head shaping, disorganization of the cell organelles, and entrapped tails in the cytoplasmic droplet. In summary, SSMEM1 is crucial for intracellular Golgi movement to ensure proper spatiotemporal formation of the sperm head that is required for fertilization. These studies and the pathway in which SSMEM1 functions have implications for human male infertility and identifying potential targets for nonhormonal contraception.

Funder

Bill & Melinda Gates Foundation

Japan Society for the Promotion of Science Overseas Research Fellowship and Lalor Foundation

National Institute of General Medical Sciences

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Takeda Science Foundation

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Ministry of Education, Culture, Sports, Science and Technology

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,General Medicine,Reproductive Medicine

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5. Genome engineering uncovers 54 evolutionarily conserved and testis-enriched genes that are not required for male fertility in mice;Miyata;Proc Natl Acad Sci USA,2016

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