Signaling networks controlling organ growth and tissue patterning - Project Summary/Abstract The overall goal of this application is to advance understanding of cellular signaling networks controlling organism development. We will investigate three signaling systems that represent different regulatory mechanisms but are united by a common theme: these pathways control key developmental processes of organ growth and tissue patterning. Specifically, we will study signaling events downstream of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway, regulation of Hippo signaling, and the functions of the kinase Minibrain/DYRK1A. We are using the advantages of the fruit fly Drosophila to investigate these mechanisms, however the knowledge generated in these studies is relevant for human biology due to the deep evolutionary conservation of the regulatory mechanisms and relevant molecules. Dysregulation of all three pathways in humans results in diseases ranging from cancer to neurodevelopmental disorders. Our approach is based on exciting preliminary data suggesting new avenues in the study of these pathways and relies on a combination of biochemical methods such as affinity purification-mass spectrometry (AP-MS) and advanced genetic and imaging assays. In Research Direction 1, we will investigate ERK-mediated downregulation of the transcriptional repressor Capicua and define its network of corepressors and chromatin regulators. In Research Direction 2, we will study two novel modes of regulation of Hippo signaling: one is centered on CG14767, an uncharacterized membrane protein that is likely involved in endolysosomal regulation, and the second includes Spenito (Nito), which is a component of RNA splicing and modification machinery that modulates Hippo signaling in an unknown way, likely via interactions with other RNA binding proteins. In Research Direction 3, we will elucidate the regulation of brain and epithelial development by the Minibrain/Rala signaling network that we recently uncovered. The proposed research will establish general regulatory principles in these signaling networks that converge to regulate organ growth and tissue patterning in development.
