Each cell independently interprets extracellular signals to decide its fate. An outstanding question in developmental biology is how these decisions are coordinated across the developing tissue primordium to produce a functional organ of appropriate size. Extracellular signals called morphogens are a critical mechanism to regulate cell fates across an entire primordium, and multiple morphogen signals are coordinated during development and in adult tissue self- renewal. The research proposed here will address interactions between morphogens in the transforming growth factor ? (TGF?) family and those that stimulate the receptor tyrosine kinase (RTK) pathway. We will use genetic methods to investigate interactions in whole tissues, while the tiisue grows or reorganizes. The model genetic organism Drosophila is used, because of the low level of genetic redundancy and the powerful tools available for in vivo experiments. Within a cell, TGF? signals are interpreted by Smad signal transduction pathways. We primarily focus on one class of TGF? signals, the bone morphogenetic proteins (BMPs). Different levels of extracellular BMP activity stimulate different levels of nuclear Smads, thus determining the genes that are expressed. In addition, protein kinases stimulated by RTK signals can modulate the levels of nuclear Smads, which may alter the way that cells respond to BMP signals. Preliminary data suggest that RTK signals down-regulate the BMP- specific fly Smad Mad and the general fly Smad Medea.
Aims 1 and 2 test the importance of this regulation during tissue growth and migration.
Aim 3 will screen for new mechanisms that regulate BMP pathway activity upstream of Smads. The molecular components of these pathways are strongly conserved between flies and humans, so we anticipate that new mechanisms will be conserved as well. Thus, this work will be important to understand the underlying mechanisms associated with TGF? dysfunction in human fibrosis, tumorigenesis, and vascular function.
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