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First published online 2 October 2008
doi: 10.1242/dev.025361

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Frs2-deficiency in cardiac progenitors disrupts a subset of FGF signals required for outflow tract morphogenesis

¹ 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.
² Department of Pediatrics and Neurobiology and Anatomy, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
³ Center for Molecular Development and Disease, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Boulevard, Houston, TX 77030, USA.

^* Author for correspondence (e-mail: fwang{at}ibt.tmc.edu)

Accepted 12 September 2008

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 FRS2 (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 Frs2 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, Frs2 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.

Key words: Receptor tyrosine kinase, Cell signaling, Heart development, Second heart field, Mouse model

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