A conserved G1 regulatory circuit promotes asynchronous behavior of nuclei sharing a common cytoplasm

Synthesis and accumulation of conserved cell cycle regulators such as cyclins are thought to promote G(1)/S and G(2)/M transitions in most eukaryotes.(1) When cells at different stages of the cell cycle are fused to form heterokaryons, the shared complement of regulators in the cytoplasm induces the nuclei to become synchronized.(2) However, multinucleate fungi often display asynchronous nuclear division cycles, even though the nuclei inhabit a shared cytoplasm.(3) Similarly, checkpoints can induce nuclear asynchrony in multinucleate cells by arresting only the nucleus that receives damage.(4-6) The cell biological basis for nuclear autonomy in a common cytoplasm is not known. Here we show that in the filamentous fungus Ashbya gossypii, sister nuclei born from one mitosis immediately lose synchrony in the subsequent G(1) interval. A conserved G(1) transcriptional regulatory circuit involving the Rb-analogue Whi5p promotes the asynchronous behavior yetWhi5 protein is uniformly distributed among nuclei throughout the cell cycle. The homologous Whi5p circuit in S. cerevisiae employs positive feedback to promote robust and coherent entry into the cell cycle. We propose that positive feedback in this same circuit generates timing variability in a multinucleate cell. These unexpected findings indicate that a regulatory program whose products ( mRNA transcripts) are translated in a common cytoplasm can nevertheless promote variability in the individual behavior of sister nuclei.