Frs2alpha-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis.
The cardiac outflow tract (OFT) is a developmentally complex structure derived from multiple lineages and is often defective in human congenital anomalies. Although emerging evidence shows that fibroblast growth factor (FGF) is essential for OFT development, the downstream pathways mediating FGF signaling in cardiac progenitors remain poorly understood. Here, we report that FRS2alpha (FRS2), an adaptor protein that links FGF receptor kinases to multiple signaling pathways, mediates crucial aspects of FGF-dependent OFT development in mouse. Ablation of Frs2alpha in mesodermal OFT progenitor cells that originate in the second heart field (SHF) affects their expansion into the OFT myocardium, resulting in OFT misalignment and hypoplasia. Moreover, Frs2alpha mutants have defective endothelial-to-mesenchymal transition and neural crest cell recruitment into the OFT cushions, resulting in OFT septation defects. These results provide new insight into the signaling molecules downstream of FGF receptor tyrosine kinases in cardiac progenitors.
Zhang
Jue
J
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA.
Lin
Yongshun
Y
Zhang
Yongyou
Y
Lan
Yongsheng
Y
Lin
Chunhong
C
Moon
Anne M
AM
Schwartz
Robert J
RJ
Martin
James F
JF
Wang
Fen
F
D000818:Animals; D019521:Body Patterning; D001934:Branchial Region / Q000196:embryology / Q000378:metabolism; D004707:Endoderm / Q000196:embryology / Q000378:metabolism; D004789:Enzyme Activation; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006321:Heart / Q000033:anatomy & histology* / Q000196:embryology*; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009024:Morphogenesis; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000201:enzymology; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
C488187:FRS2alpha protein, mouse; D008565:Membrane Proteins; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D020928:Mitogen-Activated Protein Kinases