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.
|Nie, Yingchao; Li, Qi; Amcheslavsky, Alla et al. (2015) Bunched and Madm Function Downstream of Tuberous Sclerosis Complex to Regulate the Growth of Intestinal Stem Cells in Drosophila. Stem Cell Rev 11:813-25|
|Vargas, Vladimir E; Kaushal, Kanchan M; Monau, Tshepo R et al. (2013) Extracellular signal-regulated kinases (ERK1/2) signaling pathway plays a role in cortisol secretion in the long-term hypoxic ovine fetal adrenal near term. Am J Physiol Regul Integr Comp Physiol 304:R636-43|
|Peterson, Aidan J; Jensen, Philip A; Shimell, MaryJane et al. (2012) R-Smad competition controls activin receptor output in Drosophila. PLoS One 7:e36548|
|Raftery, Laurel A; Umulis, David M (2012) Regulation of BMP activity and range in Drosophila wing development. Curr Opin Cell Biol 24:158-65|
|Brooks, Alexander; Dou, Wei; Yang, Xiaoying et al. (2012) BMP signaling in wing development: A critical perspective on quantitative image analysis. FEBS Lett 586:1942-52|
|Vargas, Vladimir E; Kaushal, Kanchan M; Monau, Tshepo et al. (2011) Long-term hypoxia enhances cortisol biosynthesis in near-term ovine fetal adrenal cortical cells. Reprod Sci 18:277-85|
|Wu, Xiaodong; Tanwar, Pradeep Singh; Raftery, Laurel A (2008) Drosophila follicle cells: morphogenesis in an eggshell. Semin Cell Dev Biol 19:271-82|
|Gluderer, Silvia; Oldham, Sean; Rintelen, Felix et al. (2008) Bunched, the Drosophila homolog of the mammalian tumor suppressor TSC-22, promotes cellular growth. BMC Dev Biol 8:10|
|Wu, Xiaodong; Yamada-Mabuchi, Megumu; Morris, Erick J et al. (2008) The Drosophila homolog of human tumor suppressor TSC-22 promotes cellular growth, proliferation, and survival. Proc Natl Acad Sci U S A 105:5414-9|
|Miles, Wayne O; Jaffray, Ellis; Campbell, Susan G et al. (2008) Medea SUMOylation restricts the signaling range of the Dpp morphogen in the Drosophila embryo. Genes Dev 22:2578-90|
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