An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart.
In order to understand how secreted signals regulate complex morphogenetic events, it is crucial to identify their cellular targets. By conditional inactivation of Fgfr1 and Fgfr2 and overexpression of the FGF antagonist sprouty 2 in different cell types, we have dissected the role of FGF signaling during heart outflow tract development in mouse. Contrary to expectation, cardiac neural crest and endothelial cells are not primary paracrine targets. FGF signaling within second heart field mesoderm is required for remodeling of the outflow tract: when disrupted, outflow myocardium fails to produce extracellular matrix and TGFbeta and BMP signals essential for endothelial cell transformation and invasion of cardiac neural crest. We conclude that an autocrine regulatory loop, initiated by the reception of FGF signals by the mesoderm, regulates correct morphogenesis at the arterial pole of the heart. These findings provide new insight into how FGF signaling regulates context-dependent cellular responses during development.
Park
Eon Joo
EJ
Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA.
Watanabe
Yusuke
Y
Smyth
Graham
G
Miyagawa-Tomita
Sachiko
S
Meyers
Erik
E
Klingensmith
John
J
Camenisch
Todd
T
Buckingham
Margaret
M
Moon
Anne M
AM
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001158:Arteries / Q000196:embryology* / Q000378:metabolism; D019898:Autocrine Communication; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D001934:Branchial Region / Q000196:embryology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D017353:Gene Deletion; D018628:Gene Dosage; D006321:Heart / Q000196:embryology*; D019426:Integrases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology* / Q000378:metabolism*; D051379:Mice; D009024:Morphogenesis; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009432:Neural Crest / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016212:Transforming Growth Factor beta; D051524:Fibroblast Growth Factor 8; D005346:Fibroblast Growth Factors; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse; C045073:Cre recombinase; D019426:Integrases