Promoter Mutation in Ccna2 Reveals Novel Functions of the Protein in Spermatogenesis

Abstract

Cyclin A2 (Ccna2/CCNA2), is a regulatory protein that plays a key role in proliferating cells, particularly in the stage of the cell cycle in which DNA is replicated (S-phase). Its expression is under the influence of E2Fs, a set of transcription factors that control the oscillating expression of cell cycle-related genes by binding to DNA sequences in their promoter region. The importance of the precise timing and level of E2F-driven Ccna2 expression has not been studied in vivo. To evaluate this interaction, we have generated a knock-in mouse line with a Ccna2 gene that has its putative E2F site disabled. Although mice homozygous for the promoter mutation are viable and healthy, we observed infertility in males. Examination of the testes revealed a three-fold decrease in testes weight in adult mice, while histological analysis of the testes revealed a progressive loss of differentiating spermatocytes in neonatal mice and a partial recuperation in adults. This project aims to elucidate the mechanistic functions of E2F-mediated regulation of Ccna2 in spermatogenesis to further understand the regulatory processes of the cell cycle.