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TGFβ SUPERFAMILY SIGNALING IS ESSENTIAL FOR THE HEART
DEVELOPMENT.
by
Somyoth Sridurongrit
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PATHOBIOLOGY)
May 2008
Copyright 2008 Somyoth Sridurongrit
Object Description
| Title | TGFbeta superfamily signaling is essential for the heart development |
| Author | Sridurongrit, Somyoth |
| Author email | sriduron@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Pathobiology |
| School | Keck School of Medicine |
| Date defended/completed | 2008-03-21 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-04-18 |
| Advisor (committee chair) | Kaartinen, Vesa |
| Advisor (committee member) |
Hinton, David R. Widelitz, Randall B. Bellusci, Saverio Liu, Yi-Hsin |
| Abstract | Transforming growth factor betas (Tgfbetas) and Bone morphogenetic proteins (Bmps) are pleiotropic cytokines involved in many developmental processes. Organ explant studies have revealed specific roles for Tgfbeta/Bmp ligands in endothelial-mesenchymal transformations (EMT) during the formation of endocardial cushions, precursors of heart valves and septa, and in epicardial-mesenchymal transformations essential for coronary vasculature development. Gene targeting studies in mice demonstrated that the Tgfbetas/Bmps are involved in the ventricular myocardial development and formation of the neural crest-derived aorticopulmonary septum. Tgfbeta/Bmp ligands signal through a repertoire of type I and type II serine/threonine kinase receptors. In our studies, we sought to determine the requirement of Bmp type I receptor Alk2 and Tgfbeta; type I receptor Alk5 for heart development by ablating these receptors specifically in the endocardium (Tie2-Cre), in the myocardium (alphaMHC-Cre and Nkx2.5-Cre), in the epicardium and endocardial cushion mesenchyme (Gata5-Cre), and in the neural crest (Wnt1-Cre). Deletion of Alk2 or Alk5 in the myocardium did not cause any obvious cardiac defects. Mutant embryos lacking Alk2 or Alk5 in endocardial cells display defective EMT during atrioventricular cushion transformation. Alk2/Wnt1-Cre mutant embryos suffer from persistent truncus arteriosus (PTA), which is due to defects in neural crest cell migration to a proximal part of the OFT. While Alk5/Gata5-Cre mutant embryos exhibit abnormal development of the epicardium that leads to defects in the ventricular myocardial proliferation and to an increased number of capillaries in the myocardium, Alk2/Gata5-Cre mutant embryos display AV valve defects, which are derived from the deficient proliferation and differentiation of the endocardial cushion mesenchyme. However, both Alk2/Gata5-Cre and Alk5/Gata5-Cre share a common aortic valve defect.; Our data indicate that Alk2- and Alk5-mediated signaling is required in endocardial cells, epicardial cells and neural crest cells for different aspects of mammalian cardiovascular development, although both receptors are dispensable in cardiomyocytes. |
| Keyword | TGFbeta; heart development |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Type | texts |
| Legacy record ID | usctheses-m1160 |
| Contributing entity | University of Southern California |
| Rights | Sridurongrit, Somyoth |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-Sridurongrit-20080418 |
| Archival file | uscthesesreloadpub_Volume26/etd-Sridurongrit-20080418.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@lib.usc.edu |
| Full text | TGFβ SUPERFAMILY SIGNALING IS ESSENTIAL FOR THE HEART DEVELOPMENT. by Somyoth Sridurongrit A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (PATHOBIOLOGY) May 2008 Copyright 2008 Somyoth Sridurongrit |
