Differential activation of the DNA replication checkpoint contributes to asynchrony of cell division in C-elegans embryos

Background: Acquisition of lineage-specific cell cycle duration is a central feature of metazoan development. The mechanisms by which this is achieved during early embryogenesis are poorly understood. In the nematode Caenorhabditis elegans, differential cell cycle duration is apparent starting at the two-cell stage, when the larger anterior blastomere AB divides before the smaller posterior blastomere P-1. How anterior-posterior (A-P) polarity cues control this asynchrony remains to be elucidated. Results: We establish that early C. elegans embryos possess a hitherto unrecognized DNA replication checkpoint that relies on the PIl-3-like kinase atl-1 and the kinase chk-1. We demonstrate that preferential activation of this checkpoint in the P-1 blastomere contributes to asynchrony of cell division in two-cell-stage wildtype embryos. Furthermore, we show that preferential checkpoint activation is largely abrogated in embryos that undergo equal first cleavage following inactivation of Galpha signaling. Conclusion: Our findings establish that differential checkpoint activation contributes to acquisition of distinct cell cycle duration in two-cell-stage C. elegans embryos and suggest a novel mechanism coupling asymmetric division to acquisition of distinct cell cycle duration during development.