LIN-12/Notch proteins are receptors that mediate cell-cell interactions that specify cell fate during animal development. Studies of LIN-12/Notch proteins are directly relevant to understanding the molecular mechanisms underlying two serious and common human diseases. Constitutive activation of LIN-12/Notch proteins has been associated with the development of certain cancers in human patients and in mammalian models, and the activity of a key component of the LIN-12/Notch signal transduction pathway, presenilin, is central to the development of Alzheimer's disease. Other, less common, diseases have also been associated with aberrations in LIN-12/Notch pathway components. Our work on lin-12 in C. elegans has contributed to the current state of understanding of conserved developmental roles and molecular mechanisms of LIN-12/Notch proteins. This proposal is concerned with identifying and characterizing new genes that influence lin-12 activity in C. elegans. Our first specific aim encompasses new variations on a proven genetic screen, based on suppression of phenotypes associated with constitutive lin-12 activation [lin-12 (d) alleles]. Our second specific aim is concerned with the basic characterization of new sel [suppressor/enhancer of lin-12] genes, and our third specific aim is concerned with understanding how the new genes we identify work together. The last two specific aims are involved with the LIN-12-mediated lateral signaling during vulval precursor cell specification.
The fourth aim i s concerned with identifying and characterizing the ligand for LIN-12 in this signaling event, and the fifth aim is concerned with characterizing a gene that may be involved in the interplay between Ras-mediated vulval induction and LIN-12-mediated lateral signaling. When these specific aims are completed, we hope to have identified conserved components and illuminated fundamental mechanisms of the regulation and execution of LIN-12/Notch signaling in animal development.
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