Interpreting Hedgehog Signaling Gradients With Cis-Regulatory DNA: A Quantitative In Vivo/Computational Approach

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

Intellectual Merit: The Hedgehog pathway is an ancient cell-cell signaling pathway by which cells communicate their position and developmental state to one another. Hedgehog signaling acts though the Gli family of transcription factors, which bind to regulatory DNA sequences called enhancers to activate or repress the expression of specific target genes. In order to understand the cell's responses to Hedgehog signaling, it is important to identify direct Gli target genes in the genome, and to understand how their expression is controlled by signaling. By integrating quantitative measurements of gene expression in the fruit fly Drosophila with computational modeling of transcriptional responses, this project will identify important mechanisms of transcriptional control by Hedgehog signaling, and will have immediate applications for strategies to identify new pathway targets. Furthermore, these principles may apply to other major signaling pathways, such as the Notch, Wnt, and nuclear receptor pathways, which, like Hedgehog, are found in animals from insects to humans. The interdisciplinary objectives of the project are to: (1) Functionally define the properties of Gli binding sites that control transcriptional responses to Hedgehog signaling; and (2) Directly integrate computational and experimental approaches to identify key regulatory mechanisms under the control of Hedgehog signaling. Broader Impacts: The project will positively impact science education, scientific training/mentorship, and diversity in the sciences, in several respects. First, the experiments and computational work will form the basis for training postdoctoral and graduate trainees, including those from underrepresented minority communities. Second, the project includes objectives that will be accomplished by undergraduate researchers and high-school volunteers, including those from underrepresented groups, and incorporates scientific and professional training for these early-stage students. Third, results from the project will be directly incorporated into new teaching tools in an innovative developmental biology course, aimed at early-stage graduate students and advanced undergraduates.