FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity.
BACKGROUND
Although the fibroblast growth factor (FGF) signaling axis plays important roles in heart development, the molecular mechanism by which the FGF regulates cardiogenesis is not fully understood.


OBJECTIVE
To investigate the mechanism by which FGF signaling regulates cardiac progenitor cell differentiation.


RESULTS
Using mice with tissue-specific ablation of FGF receptors and FGF receptor substrate 2α (Frs2α) in heart progenitor cells, we demonstrate that disruption of FGF signaling leads to premature differentiation of cardiac progenitor cells in mice. Using embryoid body cultures of mouse embryonic stem cells, we reveal that FGF signaling promotes mesoderm differentiation in embryonic stem cells but inhibits cardiomyocyte differentiation of the mesoderm cells at later stages. Furthermore, we also report that inhibiting FRS2α-mediated signals increases autophagy and that activating autophagy promotes myocardial differentiation and vice versa.


CONCLUSIONS
The results indicate that the FGF/FRS2α-mediated signals prevent premature differentiation of heart progenitor cells through suppressing autophagy. The findings provide the first evidence that autophagy plays a role in heart progenitor differentiation.
Center for Cancer and Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030-3303, USA.
Jue
J
Zhang
Junchen
J
Liu
Yanqing
Y
Huang
Julia Y F
JY
Chang
Leyuan
L
Liu
Wallace L
WL
McKeehan
James F
JF
Martin
Fen
F
Wang
D000818:Animals; D001343:Autophagy; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D046149:Embryo Culture Techniques; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006321:Heart / Q000196:embryology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000172:deficiency / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques
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