Cell Progression Through Meiosis: A Signal from Recombination to the First Division

University Of Iowa, Iowa City IA

Investigators

Abstract

Meiosis, the special division process in eukaryotes wherein chromosome number is reduced from diploid to haploid during the production of gametes, is complex and highly conserved. It is possible to think of the various steps of meiosis somewhat like an intracellular developmental pathway. Mitotic cells get a signal to enter meiosis and must go through premeiotic DNA synthesis, recombination and synapsis, reductional division, equational division, and packaging of the haploid nuclei in the proper order. An interesting and important question is how the various steps of meiosis communicate with each other to ensure that they occur at the right time and in the right sequence. In the budding yeast, Saccharomyces cerevisiae, answers to some of the questions are known. A key feature ensuring that events occur properly is ordered transcriptional regulation. Entry into meiosis involves the loss of a mitotic repressor (RME1) and expression of a meiotic activator (IME1). This results in the transcription of the "Early Meiotic Genes", which include the genes necessary for meiotic recombination. These early events activate a second transcriptional regulator, NDT80, which is required for expression of the "Middle Meiotic Genes" and the first and second meiotic division. NDT80 activation also results in the expression of "Late Meiotic Genes", though it is not yet completely clear whether this is direct or/and a consequence of NDT80 activation of the Middle genes. A second layer of regulation in meiosis is meiotic checkpoints. For example, a failure to perform premeiotic replication results in cell arrest. Recent interest has been stimulated by the realization that cells also have a checkpoint that assesses the state of meiotic recombination. In certain recombination mutants (e.g., dmc1) blocked at intermediate points in the meiotic recombination pathway, the cell arrests before the first division. This arrest requires several genes (e.g., RAD17, MEC1 ) known to be involved in mitotic DNA damage recognition checkpoints. It has been proposed that this checkpoint assessing the state of recombination is a key feature of normal progression through meiosis and that the "dmc1 checkpoint" also occurs in wildtype cells, as the intermediate is made normally during recombination. It makes good sense that the high frequency of breaking and rejoining chromosomes during recombination is a process which the cell should be able to sense. Attempts to segregate chromosomes before recombination was finished would be disastrous. There is yet another mode whereby meiotic recombination communicates with the first division, and that this communication occurs as recombination starts in wild type cells. It has been shown that meiotic cells are capable of recognizing that recombination has been started; the response is to delay the first division for a time equivalent to the time necessary to accomplish recombination. Null mutations in four genes required to initiate recombination ("EE" genes) result in a earlier first division. This is intuitively pleasing; it seems eminently reasonable that starting the complex process of recombination should signal the next meiotic step, the first division. It appears that this signaling process is complex since null mutations in different EE genes can have somewhat different effects on the timing of the first division. It has been shown that the signal is not the formation of double strand breaks (the first easily observed DNA intermediate in recombination initiation). The importance of this initiation signal is indicated by noting that, in its absence, the first division occurs at the time when homologs would normally be recombining. This indicates that the first division segregation apparatus can be ready and functional considerably earlier than it normally acts. Data from this laboratory indicates that the start of recombination prevents this premature division. This project asks how this novel signal from recombination to the first division works. Does it require the majority of the initiation genes, consistent with the idea that the signal is the formation of an initiation complex? What is the role of the synaptonemal complex and its component parts in sending the signal? Is the normal signal from recombination initiation recognized and communicated by the checkpoint genes that also respond to the dmc1 mutant block which occurs at later stages? Does the signal work by affecting activation of the central meiotic regulator NDT80? Finally, what are the other genes involved in this signal from recombination to the first division? This work will define how this intracellular signaling process, crucial for the proper progression through meiosis, functions to ensure that two critical steps in meiosis happen at the proper times.