Browsing by Subject "Receptor, Platelet-Derived Growth Factor alpha"
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Item Mesothelial and Mural Cell Contribution to Vascular Development through PDGF Signaling(2009-06-17) French, Wendy Joy; Tallquist, MichelleVascular development during embryogenesis and adulthood occurs through vasculogenesis and angiogenesis. Vasculogenesis is the de novo formation of blood vessels from mesoderm precursor cells. Angiogenesis is the formation of new vessels from existing vessels. Both processes involve hematopoietic, endothelial, and mural cells for the formation of mature, stable vasculature. While hematopoietic and endothelial cell contributions and function in vascular development have been extensively studied identifying the VEGF and TGF families as major contributors, the role of mural cells has not been clearly defined. The platelet derived growth factor beta (PDGFR beta) is essential for mural cell recruitment and expansion. Deletion of PDGFR beta leads to perinatal lethality resulting from vascular defects attributed to severe decreases in mural cells. PDGFR beta is a receptor tyrosine kinase with high homology in signal activation to PDGFR alpha. Downstream signaling pathway activation includes PI3 kinase, Src, RasGAP, Grb2, Shp-2, and PLC?gamma for the regulation of cellular functions.The focus of this research was to determine the temporal and functional requirements of PDGFR signaling in mural cells. To address the temporal requirements for PDGFR beta, genetic manipulation was used to delete the receptor in precursor and differentiated mural cells. In addition, mutant mice were generated with the additional deletion of PDGFR alpha to address the potential for compensatory or cooperative function between the two receptors. These studies identified a cooperative role for PDGFR?alpha and PDGFR beta in yolk sac mesothelial cells. Mutant mice were lethal around E10.5 with disrupted yolk sac vascular remodeling and extracellular matrix composition. The PDGFR regulate collagen matrix through regulation of matrix metalloproteinase activity and thus disrupt integrin activation. The functional role of PDGFR?beta in mural cells was addressed by signaling point mutants targeting and disrupting specific downstream pathways. These studies resulted in a progressive decrease in mural cells that correlated to the number of disrupted PDGFR-beta signaling pathways. Together these analyses demonstrate PDGFR and mural cells are essential for vascular development and maintenance.Item PDGFR Alpha Signaling Requirements in the Development of Tissues Derived From Sclerotome and Dermatome(2007-05-23) Pickett, Elizabeth Ann; Tallquist, MichelleThe Platelet-Derived Growth Factor Receptors (PDGFR) play roles in the development of multiple mesenchymal cell types. Upon ligand binding, the receptors signal through a number of intracellular signaling molecules and elicit many cellular responses including migration, proliferation, and differentiation. Studies utilizing tissuespecific deletion permit the elucidation of cell autonomous phenotypes, while analysis of signaling point mutants permits identification of the function of specific downstream effectors. My studies use both methods to uncover the role of PDGFRalpha signaling in the development of skin and bone. An unexplained phenotype of PDGFRalpha null embryos is a defect in the axial skeletal that leads to spina bifida. Using conditional gene deletion I determined that the population of cells responsible for this phenotype is not the chondrocyte but is instead another derivative of the sclerotome. These results demonstrate that signals from adjacent tissues can play important roles in the differentiation of bone populations and identifies an etiology for spina bifida that is not directly caused by neural tube or bone defects. Interestingly, loss of PI3K signaling downstream of PDGFRalpha also results in spina bifida. I found that the sclerotome population described above requires PDGFRalpha signaling to migrate dorsal to the neural tube via PI3K activation. Without this signaling event, downstream effectors including Akt, p70S6K, and PAK1 are not activated and the cells fail to form Rac-associated membrane ruffles. This is the first in vivo evidence that PI3K driven pathways are required for migration downstream of the PDGFRalpha .