Endocardial and epicardial derived FGF signals regulate myocardial proliferation and differentiation in vivo.
The epicardium regulates growth and survival of the underlying myocardium. This activity depends on intrinsic retinoic acid (RA) and erythropoietin signals. However, these signals do not act directly on the myocardium and instead are proposed to regulate the production of an unidentified soluble epicardial derived mitogen. Here, we show that Fgf9, Fgf16, and Fgf20 are expressed in the endocardium and epicardium and that RA can induce epicardial expression of Fgf9. Using knockout mice and an embryonic heart organ culture system, we show that endocardial and epicardial derived FGF signals regulate myocardial proliferation during midgestation heart development. We further show that this FGF signal is received by both FGF receptors 1 and 2 acting redundantly in the cardiomyoblast. In the absence of this signal, premature differentiation results in cellular hypertrophy and newborn mice develop a dilated cardiomyopathy. FGFs thus constitute all or part of the epicardial signal regulating myocardial growth and differentiation.
Lavine
Kory J
KJ
Department of Molecular Biology and Pharmacology, Washington University Medical School, St. Louis, MO 63110, USA.
Yu
Kai
K
White
Andrew C
AC
Zhang
Xiuqin
X
Smith
Craig
C
Partanen
Juha
J
Ornitz
David M
DM
D000367:Age Factors; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects*; D004622:Embryo, Mammalian; D051525:Fibroblast Growth Factor 9; D005346:Fibroblast Growth Factors / Q000145:classification / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D006321:Heart / Q000196:embryology; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009924:Organ Culture Techniques / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D014212:Tretinoin; D005346:Fibroblast Growth Factors; D001973:Bromodeoxyuridine