The highly conserved LAMMER/CLK2 protein kinases prevent germ cell overproliferation in Drosophila

Germ cells undergo proper mitotic amplification before entering meiosis. The mitosis/meiosis switch drives the germ cells to leave the potential stem cell pool and become terminally differentiated. This important process is tightly controlled in the spermatogenesis of all animals. However, a unifying mechanism has yet to be unraveled. Drosophila spermatogenesis is an ideal system to dissect the regulatory program of the mitosis/meiosis switch. The timely accumulation of the pro-differentiation factor Bam has been shown to be central in this process. In a Drosophila genetic screen, we discovered that the mutations in Doa, a gene encoding a member of the highly conserved LAMMER/Cdc2-like kinase (CLK) family, cell-autonomously induced the germ cell overproliferation due to the failed transition from mitosis to meiosis. Additional Bam expression in Doa mutant germline promoted the differentiation from the mitotic to the meiotic state. Remarkably, the human or murine CLK2 could prevent the germline overproliferation and even restore the fertility of Doa mutant flies. Such rescuing activity of Doa or its human homolog requires a conserved residue in their predicted kinase catalytic domain. We propose that LAMMER/Cdc2-like kinase, represented by Doa and its mammalian homolog CLK2, is a critical and conserved component in the regulatory program of the mitosis-to-meiosis switch.