A central question in developmental biology is how a cell interprets extracellular signals to make cell fate decisions. The research proposed here will address this question for TGFbeta signaling, and seek to understand how the two types of TGFa signals are integrated with each other and with receptor tyrosine kinase (RTK) signals. 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, TGFbeta signals are interpreted through two Smad signal transduction pathways, a BMP Smad pathway and an Activin Smad pathway. The molecular components of these pathways are strongly conserved between flies and humans, and many of the basic developmental functions for BMP signaling are conserved as well. Activin signaling is poorly understood in flies, and the physiological basis for evolutionary conservation is unknown. New strong and weak mutations in smox, the Smad gene that is thought to transduce fly Activin signals, will be characterized under Aim 3. Two hypotheses for the function of this R-Smad and the fly Activin receptor Babo are tested under Aim 3: first, that they are general regulators of proliferation, and second, that they have an early role in patterning the wing primordium. Smad activity as transcription factors is induced by TGFbeta signals; these proteins are cytoplasmic in the absence of a signal and nuclear in stimulated cells. An emerging model is that different levels of extracellular signal activity stimulate different levels of nuclear Smads, thus determining the genes that are expressed. However, some data suggest that protein kinases stimulated by RTK signals can also modulate the levels of nuclear Smads. Preliminary data suggest that RTK signals down-regulate the BMP-specific fly Smad Mad and the general fly Smad Medea. Strong regulation of Mad is detected in a different region from the region where strong regulation of Medea is detected.
Aim 1 tests the hypothesis that both Smads are regulated by the epidermal growth factor RTK pathway.
Aim 2 tests the hypothesis that regulation of Medea activity alters both activin and BMP responses. Medea is the functional ortholog of the human tumor suppressor gene DPC4 (Deleted in Pancreatic Cancer4), which encodes the human general Smad, Smad4. These studies will contribute to understanding the functions of human Smad4, and to understanding other aspects of Smad activity that may be important for TGFbeta dysfunction in human fibrosis, tumorigenesis, and vascular function.
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