Meiosis plays a central role in the sexual reproduction of nearly all eukaryotes. The major genetic events of recombination and chromosome segregation that occur during its two cell divisions are critical for generating genetic diversity and producing offspring with normal chromosome numbers. The overall objective of our research program is to understand the genetic mechanisms that govern meiotic development. Our long range goals are to determine the structure, function, and regulation of selected meiosis-specific genes required for chromosome exchange and segregation, and to use these genes to uncover critical regulatory functions that specify the orderly progression of meiotic events. Of special interest is the relationship between meiotic and mitotic cell division controls and the extent to which they interact.
The specific aims address: 1) the mechanism of action and order of function of three key meiosis-specific genes (SPO11, SPO12, and SPO13) that regulate recombination, segregation, and the timing of nuclear division during meiosis, and 2) their developmental regulation during mitosis and meiosis. The unicellular eukaryote, Saccharomyces cerevisiae, is employed as a model system for these studies. The experimental approach utilizes new loss and gain of function mutants and wild type overexpressorss to test specific models of how these genes function, interact with one another, and interface with selected mitotic cell cycle genes (CDCs, CLNs, and CLBs). Target and effectors will be sought by novel selection schemes to detect suppressors and the expression dependency of other meiotic genes as well as by standard two-hybrid and synthetic lethal analysis. The protein products of specific genes (particularly Spo12, Spol3, and Ume6) will be localized and examined for their synthesis, modification and stability during mitosis and meiosis to integrate genetic findings with molecular analysis in deducing their specific functions. Additional studies will be undertaken to determine the regulation and mechanism of action of Ume6 and to identify factors which interact with this critical regulator to control expression of meiosis-specific genes. Most of the loci under study have been cloned, sequenced, and their pattern of transcription defined; antibodies to Spol3 and Ume6 are available and are being prepared for other relevant proteins. It is anticipated that these studies will help uncover a complex series of events affecting chromosome behavior into a successful developmental pathway. Analysis of the mechanisms that govern cell division and differentiation, and the factors essential for exchange and segregation should contribute significantly to understanding cell division control, malignancy, and reproductive diseases associated with instability and abnormal chromosome transmission.
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