Edward Winter, PhD

Defects in meiotic regulation are a significant cause of infertility, birth defects, spontaneous abortion, and disease. The Winter laboratory studies mechanisms that regulate meiotic development using the yeast Saccharomyces cerevisiae as a model system. Our current work is focused on two major areas of investigation

1- The transcriptional cascade of meiosis. Transcriptional cascades are ubiquitous in biological systems. They play a particularly prominent role in controlling cellular differentiation programs. The transcriptional program of meiosis consists of 3 major sets of genes termed early, middle and late. Early genes are involved in meiotic S-phase, homolog pairing, synaptonemal complex formation, and genetic recombination. Middle genes control the nuclear divisions and gametogenesis (spore formation). Late genes control spore maturation. These 3 sets of genes are further temporally diversified to yield as many as 12 subsets that are expressed as different steps in the program are taking place. The induction of middle genes controls exit from meiotic prophase. In yeast, this transition corresponds to the commitment point, after which the inducing signal is no longer needed to complete the program. Middle promoters are controlled by a repressor protein (Sum1), that recruits a sirtuin (Hst1). In addition, a transcriptional activator (Ndt80) acts in opposition to Sum1/Hst1. Sum1 and Ndt80 compete for binding to overlapping DNA elements (termed middle sporulation elements or MSEs) and NDT80 expression is controlled by an MSE in its own promoter. These interactions form a transcriptional switch that triggers meiotic chromosome segregation, meiotic commitment, and completion of the program. This transcriptional switch is regulated by dependency and checkpoint signals. Feed-forward interactions give switch-like properties to the system. We are currently using molecular genetic approaches to define the signals that control the Sum1/Ndt80 switch and elucidate how this switch regulates meiotic progression.

2- Meiosis-specific signaling networks. A large fraction of the genes that are regulated by the transcriptional program of meiosis encode signaling molecules. The transient expression of different sets of signaling molecules allows a single cell to respond to different nutritional, cell-cycle, and dependency signals as different steps in the program are taking place. We previously described a meiosis-specific signaling network that controls multiple steps in meiotic development. Key members of this signaling network include a meiosis-specific cyclin-dependent kinase (CDK) -like kinase that superimposes meiotic regulation at multiple steps in the program (Ime2), a meiosis-specific MAPK that is uniquely required for the post-meiotic program of spore formation (Smk1), the CDK activating kinase (Cak1) that activates both Ime2 and Smk1, and a meiosis-specific targeting subunit for the anaphase-promoting complex E3 ubiquitin-ligase (Ama1). We are currently investigating how Smk1 is regulated to elucidate how meiosis is coupled to gamete formation and how the Ime2 CDK-like kinase superimposes meiotic regulation on the mitotic default pathway.

PhD, State University of New York at Stony Brook - 1985

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