Lakshmi Gopinathanl1, Radoslaw Szmyd1,2, Diana Low,1, M. Kasim Dirill1,8, Heng-Yu Chang3, Vincenzo Coppola4,9, Kui Liu5, Lino Tessarollo4, Ernesto Guccione1,7, Ans M.M. van Pelt6, and Philipp Kaldis1.7.10.*.
1 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), 61 Biopolis Drive, Proteos #3-09,
Singapore 138673, Republic of Singapore
2 NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore (NUS), Singapore 117456, Republic of
3 Department of Biochemistry and Molecular Cell Biology, School of Medicine, Taipei Medical University, Taipei 11031, Taiwan
4 Mouse Cancer Genetics Program, National Cancer Institute, NCI-Frederick, Building 560, 1050 Boyles Street, Frederick,
MD 21702-1201, USA
5 Department of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, Sweden
6 Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam,
7 Department of Biochemistry, National University of Singapore (NUS), Singapore 117597, Republic of Singapore
8 Present address: Izmir Biomedicine and Genome Institute, Dokuz Eylul University, 35340 Izmir, Turkey
9 Present address: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University,
988 Biomedical Research Tower, 460 West 12th Avenue, Columbus, OH 43210, USA
10 Lead Contact
Published in Cell Reports on 18 July 2017.
Gopinathan et al use mouse genetics to characterize the in vivo functions of Emi2, a meiotic inhibitor of APC/C. Emi2 knockout mice are sterile, revealing that Emi2 is essential for oocytes and spermatocytes to complete meiotic divisions. Impaired Cdk1 activity upon loss of Emi2 contributes to spermatogenic defects.
The meiotic functions of Emi2, an inhibitor of the APC/C complex, have been best characterized in oocytes where it mediates metaphase II arrest as a component of the cytostatic factor. We generated Emi2 knockout mice to determine its in vivo functions, in particular its functions in the testis, where Emi2 is expressed at high levels. Male and female Emi2 knockout mice are viable but sterile, indicating that Emi2 is essential for meiosis, but dispensable for embryonic development and mitotic cell divisions. We found that besides regulating cell cycle arrest in mouse eggs, Emi2 is essential for meiosis I progression in spermatocytes. In absence of Emi2, spermatocytes arrest in early diplotene of prophase I. This arrest is associated with decreased Cdk1 activity and was partially rescued by a knockin mouse model of elevated Cdk1 activity. Additionally, we detected expression of Emi2 in spermatids and sperm, suggesting potential post-meiotic functions for Emi2.
- Deletion of Emi2 leads to sterility in male and female mice
- In the absence of Emi2, oocytes exhibit defective entry into meiosis II
- Emi2KO spermatocytes are unable to complete meiotic divisions
- Elevated Cdk1 activity partially rescues the spermatogenic arrest in absence of Emi2
Emi2 is essential for mouse spermatogenesis.
Testes were stained by the Periodic Acid Schiff (PAS) technique. Cauda epididymis was stained with Hematoxylin-eosin. Spermatids are absent in Emi2 knockout testes and mature sperm are absent in Emi2KO epididymis. In the testis, open asterisks indicate normal pachytene spermatocytes, open arrows indicate normal diplotene spermatocytes, open arrow heads indicate meiotic metaphases in spermatocytes, black arrow heads indicate round spermatids, arrows indicate elongating spermatids, asterisks * indicate mono- or multi-nuclear apoptotic pachytene/diplotene spermatocytes. The round cells in the epididymis are most likely apoptotic immature germ cells. Scale bar: testis 20 µm; epididymis 50 µm. Results are representative of testes/cauda epididymis extracted from at least three mice per age/genotype.
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