Abstract
Tight regulation of developmental pathways is of critical importance to all organisms, and is achieved by a transcriptional cascade ensuring the coordinated expression of sets of genes. We aimed to explore whether a strong signal is required to enter and complete a developmental pathway, by using meiosis in budding yeast as a model. We demonstrate that meiosis in budding yeast is insensitive to drastic changes in the levels of its consecutive positive regulators (Ime1, Ime2, and Ndt80). Entry into DNA replication is not correlated with the time of transcription of the early genes that regulate this event. Entry into nuclear division is directly regulated by the time of transcription of the middle genes, as premature transcription of their activator NDT80, leads to a premature entry into the first meiotic division, and loss of coordination between DNA replication and nuclear division. We demonstrate that Cdk1/Cln3 functions as a negative regulator of Ime2, and that ectopic expression of Cln3 delays entry into nuclear division as well as NDT80 transcription. Because Ime2 functions as a positive regulator for premeiotic DNA replication and NDT80 transcription, as well as a negative regulator of Cdk/Cln, we suggest that a double negative feedback loop between Ime2 and Cdk1/Cln3 promotes a bistable switch from the cell cycle to meiosis. Moreover, our results suggest a regulatory mode switch that ensures robust meiosis as the transcription of the early meiosis-specific genes responds in a graded mode to Ime1 levels, whereas that of the middle and late genes as well as initiation of DNA replication, are regulated in a threshold mode.
Highlights
Precise and complex regulation is required for entering a developmental pathway at the correct time and in the appropriate cell type
We show that the time of transcription of NDT80 and the middle genes determines the time cells enter nuclear divisions, as premature transcription of NDT80 resulted in premature nuclear division and a reduction in asci formation
We suggest that Ime2, which controls both initiation of premeiotic DNA replication and the transcription of NDT80, serves as the regulator that switches the graded mode of transcription of the early genes to a threshold mode for regulating entry into DNA replication and the transcription of the middle genes
Summary
Precise and complex regulation is required for entering a developmental pathway at the correct time and in the appropriate cell type. Deviations from this regulation may lead to genome instability, causing either cell death or the formation of tumor cells [1]. The master activator initiating the cascade is usually controlled by multiple input signals, each with a small impact. It is the combinational nature of the induction of the master activator that ensures the correct spatial and temporal activity of the developmental pathway [2,3,4]. Whether a strong signal is essential for efficient entry into and completion of a developmental pathway and, if not, how cells cope with premature, delayed, reduced, or increased signals, remains a fundamental, unsolved question
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