Philadelphia University + Thomas Jefferson University

Winter, Edward

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Edward Winter, PhD

Contact Dr. Winter

233 South 10th Street
228 BLSB
Philadelphia, PA 19107

(215) 503-4139
(215) 503-9162 fax

Medical School

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

Expertise and Research Interests

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.

Keywords

Biological Sciences; Map Kinase; Meiosis; Microbial Genetics; Sporulation; Yeast

Publications

Most Recent Peer-Reviewed Publications

  1. Ssp2 binding activates the Smk1 mitogen-activated protein kinase
  2. Autophosphorylation of the Smk1 MAPK is spatially and temporally regulated by Ssp2 during meiotic development in yeast
  3. Multisite phosphorylation of the sum1 transcriptional repressor by s-phase kinases controls exit from meiotic prophase in yeast
  4. Activation of the smk1 mitogen-activated protein kinase by developmentally regulated autophosphorylation
  5. The Sum1/Ndt80 transcriptional switch and commitment to meiosis in Saccharomyces cerevisiae
  6. The Cdk1 and Ime2 protein kinases trigger exit from meiotic prophase in Saccharomyces cerevisiae by inhibiting the Sum1 transcriptional repressor
  7. The Ime2 protein kinase enhances the disassociation of the Sum1 repressor from middle meiotic promoters
  8. The Ras/cAMP pathway and the CDK-like kinase Ime2 regulate the MAPK Smk1 and spore morphogenesis in Saccharomyces cerevisiae
  9. Arg-Pro-X-Ser/Thr is a consensus phosphoacceptor sequence for the meiosis-specific Ime2 protein kinase in Saccharomyces cerevisiae
  10. Phosphorylation of histone H4 Ser1 regulates sporulation in yeast and is conserved in fly and mouse spermatogenesis
  11. Erratum: The Ama1-directed anaphase-promoting complex regulates the Smk1 mitogen-activated protein kinase during meiosis in yeast (Genetics (2005) 171, (901-911))
  12. Phosphorylation of Ime2 regulates meiotic progression in Saccharomyces cerevisiae
  13. Regulation of insulin-like growth factor binding protein-5, four and a half lim-2, and a disintegrin and metalloprotease-9 expression in osteoblasts
  14. The Ama1-directed anaphase-promoting complex regulates the Smk1 mitogen-activated protein kinase during meiosis in yeast
  15. Recovery capacity of glial progenitors after in vivo fission-neutron or X irradiation: Age dependence, fractionation and low-dose-rate irradiations
  16. RSC1 and RSC2 are required for expression of mid-late sporulation-specific genes in Saccharomyces cerevisiae
  17. The Cdk-Activating Kinase Cak1p Promotes Meiotic S Phase through Ime2p
  18. Sum1 and Ndt80 proteins compete for binding to middle sporulation element sequences that control meiotic gene expression
  19. CAK1 promotes meiosis and spore formation in Saccharomyces cerevisiae in a CDC28-independent fashion
  20. The pachytene checkpoint in Saccharomyces cerevisiae requires the Sum1 transcriptional repressor