Abstract
Loss of function of cyclin E1 or E2, important regulators of the mitotic cell cycle, yields viable mice, but E2-deficient males display reduced fertility. To elucidate the role of E-type cyclins during spermatogenesis, we characterized their expression patterns and produced additional deletions of Ccne1 and Ccne2 alleles in the germline, revealing unexpected meiotic functions. While Ccne2 mRNA and protein are abundantly expressed in spermatocytes, Ccne1 mRNA is present but its protein is detected only at low levels. However, abundant levels of cyclin E1 protein are detected in spermatocytes deficient in cyclin E2 protein. Additional depletion of E-type cyclins in the germline resulted in increasingly enhanced spermatogenic abnormalities and corresponding decreased fertility and loss of germ cells by apoptosis. Profound meiotic defects were observed in spermatocytes, including abnormal pairing and synapsis of homologous chromosomes, heterologous chromosome associations, unrepaired double-strand DNA breaks, disruptions in telomeric structure and defects in cyclin-dependent-kinase 2 localization. These results highlight a new role for E-type cyclins as important regulators of male meiosis.
Highlights
Cyclins are key cell cycle regulatory subunits that bind, activate, and provide substrate specificity for the cyclin-dependent kinases (CDKs)
We investigated how E-type cyclins control male meiosis by examining their expression in spermatogenesis and the consequences that multiple deletions of Ccne1 and Ccne2 alleles produce
We further found that cyclin E1 is involved in sex chromosome synapsis while E2 is involved with homologous pairing and chromosome and telomere integrity
Summary
Cyclins are key cell cycle regulatory subunits that bind, activate, and provide substrate specificity for the cyclin-dependent kinases (CDKs). The role of cyclins in the somatic mitotic cycle has been extensively studied, their function in the meiotic cycle is poorly understood. Several cyclins have been identified with unique patterns of expression during spermatogenesis [1]. The testis-specific A-type cyclin, cyclin A1, is restricted to spermatocytes during prophase I from the pachytene to diplotene stages [2]. Cyclin A1 was the first cyclin shown to be essential for meiosis: cyclin A1-deficient male mice are sterile due to an arrest in meiotic prophase at the diplotene stage, just prior to the first meiotic division [3]. Cyclin A2, which is generally considered to be the mammalian S-phase cyclin, is expressed in mitotically dividing spermatogonia but not in meiotic prophase spermatocytes [4]. Deletion of the ubiquitously expressed cyclin A2 results in embryonic lethality shortly after implantation [5]
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