期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 27, 期 15, 页码 5352-5364出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00068-07
关键词
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资金
- NHLBI NIH HHS [HL49277, R01 HL049277, HL070953, HL71266, HL-081844, R01 HL071054, R01 HL049277-14, R01 HL081844, R01 HL049277-16, R01 HL070953, R01 HL049277-15, R01 HL071266, HL-071054] Funding Source: Medline
- NINDS NIH HHS [R01 NS019090, NS19090] Funding Source: Medline
To examine a role for focal adhesion kinase (FAK) in cardiac morphogenesis, we generated a line of mice with a conditional deletion of FAK in nkx2-5-expressing cells (herein termed FAK(nk) mice). FAK(nk) mice died shortly after birth, likely resulting from a profound subaortic ventricular septal defect and associated mal-alignment of the outflow tract. Additional less penetrant phenotypes included persistent truncus arteriosus and thickened valve leaflets. Thus, conditional inactivation of FAK in nkx2-5-expressing cells leads to the most common congenital heart defect that is also a subset of abnormalities associated with tetralogy of Fallot and the DiGeorge syndrome. No significant differences in proliferation or apoptosis between control and FAK(nk) hearts were observed. However, decreased myocardialization was observed for the conal ridges of the proximal outflow tract in FAK(nk) hearts. Interestingly, chemotaxis was significantly attenuated in isolated FAK-null cardiomyocytes in comparison to genetic controls, and these effects were concomitant with reduced tyrosine phosphorylation of Crk-associated substrate (CAS). Thus, it is possible that ventricular septation and appropriate outflow tract alignment is dependent, at least in part, upon FAK-dependent CAS activation and subsequent induction of polarized myocyte movement into the conal ridges. Future studies will be necessary to determine the precise contributions of the additional nkx2-5-derived lineages to the phenotypes observed.
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