Notch is a transmembrane receptor that controls cell fate decisions throughout Drosophila development. The fact that Notch1 gene is expressed in the developing thymocytes in the mouse, together with the observation that some human T cell leukemias are associated with translocations of the Notch1 locus, prompted us to investigate the role of Notch can affect two successive cell fate decisions within the T cell lineage, the choice between CD4 and CD8 fate and the choice between the ab and gd fates. Two important areas to be addressed in the future are (1) How is Notch activity normally regulated in the thymus? and (2) How does Notch activity influence T cell fate? This proposal is designed to investigate these two areas.
AIM 1 : What is the role of Jagged2 in the thymus? The key to understanding how Notch activity is normally regulated in the thymus is the identification and characterization of thymic ligands for Notch. Ligands for Notch have a characteristic motif, termed a DLS domain, and one DSL protein, Jagged2, is expressed in the thymus. We will investigate whether Jagged2 is the ligand that regulates Notch activity during the CD4 vs. CD8 lineage choice and/or during the ab vs gd lineage choice.
AIM 2 : What is the role of HES1 and CBF1 in T cell fate decisions? In Drosophila, the Notch signaling pathway appears to act via direct activation of transcription factors. The activated Notch receptor turns on a transcription factor called Su(H) which in turns up-regulates transcriptional repressors encoded by the En(spl) complex. En(spl) repressors then turn off genes that are needed for the primary fate. We will investigate the role of the SU(H) homolog (CBF1) and an En(spl) homolog (HES1) in the Notch signaling pathway in T cells. Our long term goal is to understand what intracellular events are triggered by the interaction between Notch and its extracellular ligands and how these intracellular events influence T cell fate and tumor progression.
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