Cardiac developmental defects and eccentric right ventricular hypertrophy in cardiomyocyte focal adhesion kinase (FAK) conditional knockout mice.
Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that plays an important role in integrin-mediated signal transduction. To explore the role and mechanisms of FAK in cardiac development, we inactivated FAK in embryonic cardiomyocytes by crossing the floxed FAK mice with myosin light chain-2a (MLC2a) Cre mice, which expressed Cre as early as embryonic day 9.5 in the heart. The majority of conditional FAK knockout mice generated from MLC2a-Cre (CFKO-2a) died in the embryonic stage with thin ventricular wall and ventricular septal defects. A small fraction of CFKO-2a mice survived to adulthood with spontaneous eccentric right ventricle hypertrophy. Transmission electron microscopy analysis displayed swelling in the rough endoplasmic reticulum in CFKO-2a embryonic cardiomyocytes. We found that decreased cell proliferation, but not increased cell apoptosis or differentiation, is the reason for the thin ventricular wall in CFKO-2a mice. Microarray analysis suggests that myocyte enhancer factor 2a (MEF2a) can be regulated by FAK and that inactivation of FAK in the embryonic heart compromised MEF2a expression. Last, we found that Src, but not PI3K, is important in mediating signal transduction for the regulation of MEF2a by FAK. Together, these results identified the role and mechanisms of FAK in embryonic cardiac development.
Peng
Xu
X
Departments of Molecular Medicine, Clinical Sciences, and Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Wu
Xiaoyang
X
Druso
Joseph E
JE
Wei
Huijun
H
Park
Ann Yong-Jin
AY
Kraus
Marc S
MS
Alcaraz
Ana
A
Chen
Ju
J
Chien
Shu
S
Cerione
Richard A
RA
Guan
Jun-Lin
JL
D000818:Animals; D018376:Cardiovascular Abnormalities / Q000196:embryology* / Q000201:enzymology*; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000201:enzymology; D047108:Embryonic Development; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000172:deficiency* / Q000378:metabolism; D017353:Gene Deletion; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology*; D019426:Integrases / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018994:Myosin Light Chains / Q000378:metabolism; D009928:Organ Specificity; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis
D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; C524495:Mlc2a protein, mouse; D018006:Myogenic Regulatory Factors; D018994:Myosin Light Chains; D051416:Focal Adhesion Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); C045073:Cre recombinase; D019426:Integrases