The cytoplasmic domain of TGFβR3 through its interaction with the scaffolding protein, GIPC, directs epicardial cell behavior

Autor: Todd D. Camenisch, Anita F. Austin, Joseph D. Love, Christopher B. Brown, Evisabel A. Craig, Nora S. Sanchez, Joey V. Barnett, Cynthia R. Hill, Jonathan H. Soslow, Andras Czirok
Rok vydání: 2011
Předmět:
Cellular differentiation
medicine.medical_treatment
Coronary vessels
Coronary Vessel Anomalies
Cell
TGFβR3
Mice
0302 clinical medicine
Cell Movement
Pregnancy
Mice
Knockout
0303 health sciences
Models
Cardiovascular
Gene Expression Regulation
Developmental
Cell Differentiation
Epicardium
Cell biology
medicine.anatomical_structure
Gene Knockdown Techniques
Coronary vessel
Female
Proteoglycans
Signal transduction
Pericardium
Signal Transduction
medicine.medical_specialty
Epithelial-Mesenchymal Transition
Mice
129 Strain
Myocytes
Smooth Muscle
Biology
Time-Lapse Imaging
Article
Transforming Growth Factor beta1
03 medical and health sciences
TGFβ
Transforming Growth Factor beta2
Internal medicine
medicine
Animals
Protein Interaction Domains and Motifs
Molecular Biology
030304 developmental biology
Adaptor Proteins
Signal Transducing
Cell Proliferation
DNA Primers
Base Sequence
Cell growth
Growth factor
Neuropeptides
Cell Biology
Mice
Inbred C57BL
Endocrinology
Cytoplasm
Carrier Proteins
Receptors
Transforming Growth Factor beta
030217 neurology & neurosurgery
Transforming growth factor
Developmental Biology
Zdroj: Developmental biology. 358(2)
ISSN: 1095-564X
Popis: The epicardium is a major contributor of the cells that are required for the formation of coronary vessels. Mice lacking both copies of the gene encoding the Type III Transforming Growth Factor β Receptor (TGFβR3) fail to form the coronary vasculature, but the molecular mechanism by which TGFβR3 signals coronary vessel formation is unknown. We used intact embryos and epicardial cells from E11.5 mouse embryos to reveal the mechanisms by which TGFβR3 signals and regulates epicardial cell behavior. Analysis of E13.5 embryos reveals a lower rate of epicardial cell proliferation and decreased epicardially derived cell invasion in Tgfbr3(-/-) hearts. Tgfbr3(-/-) epicardial cells in vitro show decreased proliferation and decreased invasion in response to TGFβ1 and TGFβ2. Unexpectedly, loss of TGFβR3 also decreases responsiveness to two other important regulators of epicardial cell behavior, FGF2 and HMW-HA. Restoring full length TGFβR3 in Tgfbr3(-/-) cells rescued deficits in invasion in vitro in response TGFβ1 and TGFβ2 as well as FGF2 and HMW-HA. Expression of TGFβR3 missing the 3 C-terminal amino acids that are required to interact with the scaffolding protein GIPC1 did not rescue any of the deficits. Overexpression of GIPC1 alone in Tgfbr3(-/-) cells did not rescue invasion whereas knockdown of GIPC1 in Tgfbr3(+/+) cells decreased invasion in response to TGFβ2, FGF2, and HMW-HA. We conclude that TGFβR3 interaction with GIPC1 is critical for regulating invasion and growth factor responsiveness in epicardial cells and that dysregulation of epicardial cell proliferation and invasion contributes to failed coronary vessel development in Tgfbr3(-/-) mice.
Databáze: OpenAIRE
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