This is a revised proposal for a renewal application for 1R01GM080372 Function and regulation of the ETS transcriptional repressor TEL1/Yan. Developmental programs are driven by transcription factors that coordinate precise patterns of gene expression in response to inductive signaling cues. The goals of this proposal are to uncover the regulatory strategies that keep gene expression programs in progenitors stably off, yet poised for rapid and precise activation in response to the inductive cues that initiate cell fate specification. Specifically we will study how the action of two members of the conserved ETS family of transcription factors, a repressor Yan and an activator Pointed (Pnt), known as TEL1/ETV6 and ETS1/ETS2 in humans, orchestrates the transition from progenitor to specified cell fate in response to receptor tyrosine kinase/Ras/MAPK signaling pathway. The central hypothesis is that the activator Pointed organizes and coordinates the entire sequence of events by first cooperating with Yan to establish the initial repressed state and then working in opposition to switch the system over to activation of gene expression and adoption of cell fate.
Aim 1 explores how different Pointed isoforms determine the system's sensitivity and response to MAPK signaling.
Aim 2 will elucidate the molecular mechanisms that coordinate Pointed's dual roles as repressor and activator during the cell fate specification process. Because the ideas we are testing address fundamental mechanisms of developmental regulation, and the signaling factors and transcriptional networks we study are conserved, the discoveries that emerge will have broad impact.
The combination of unsurpassed genetic tractability and the extensive evolutionary conservation of developmental signaling networks makes Drosophila an ideal model system in which to elucidate the molecular mechanisms that ensure accurate and robust transitions from multipotent progenitor to specified cell fate. Our approach is to investigate how the coordinate action of two antagonistic transcription factors directs the changes in downstream gene expression programs needed to effect developmental transitions. Because these transcription factors have conserved functions in mammals, and because their dysregulation contributes to oncogenic transformation in a number of leukemias and solid tumors, the discoveries that emerge from our investigations will improve understanding of human development and disease.
Showing the most recent 10 out of 14 publications
