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PDGF‐signaling in the second heart field: combined evidence from human and mouse studies
Author(s) -
Bleyl Steven B,
Saijoh Yukio,
Gittenbergerde Groot Adriana C,
Shiota Kohei,
Schoenwolf Gary C
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.305.4
Subject(s) - biology , penetrance , pdgfra , genetics , platelet derived growth factor receptor , gene knockdown , embryo , microbiology and biotechnology , primitive streak , phenotype , gene , cancer research , embryogenesis , growth factor , gastrulation , receptor , gist , stromal cell
The majority of congenital heart defects (CHD) occur via the interplay of genetic and/or environmental factors and pinpointing these factors has proven problematic. We used a combined approach in humans and model organisms to identify a susceptibility factor for one such CHD, total anomalous pulmonary venous return (TAPVR). Genetic analyses in TAPVR patients and expression studies in chick and mouse implicated the PDGFRA gene in the development of TAPVR. Functional knockdown of PDGF‐signaling in both chick and mouse during the period of PV formation causes a spectrum of inflow tract defects, including TAPVR, that involve the dorsal mesocaridal protrusion (DMP) supporting a role for PDGF‐signaling in second heart field (SHF) development. Highly similar defects were found in an early stage embryo from the Kyoto human embryo collection. These defects occur with low penetrance suggesting the interaction of other genetic or environmental factors. Failure of a specific human PDGFRA BAC transgene to rescue inflow tract defects of Pdgfra null/null embryos further supports dysregulation of PDGFRA in human TAPVR. Taken together, these data from human genetics and animal models support a role for PDGF‐signaling in normal PV development and provide important insight into the embryogenesis and molecular pathogenesis of TAPVR, a CHD with complex inheritance.