Conditional deletion of focal adhesion kinase leads to defects in ventricular septation and outflow tract alignment
Conditional deletion of focal adhesion kinase leads to defects in ventricular septation and outflow tract alignment
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DOI：
10.1128/mcb.00068-07
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发表时间：
2007-08-01
影响因子：
5.3
通讯作者：
Taylor, Joan M.
中科院分区：
文献类型：
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作者：
Hakim, Zeenat S.;DiMichele, Laura A.;Taylor, Joan M.
为了研究粘着斑激酶 (FAK) 在心脏形态发生中的作用，我们产生了一系列在 nkx2-5 表达细胞中条件性删除 FAK 的小鼠（本文称为 FAK(nk) 小鼠）。 FAK(nk) 小鼠出生后不久就死亡，可能是由于严重的主动脉下室间隔缺损和相关的流出道排列不良所致。其他渗透性较低的表型包括持续性动脉干和瓣叶增厚。因此，表达 nkx2-5 的细胞中 FAK 的条件性失活会导致最常见的先天性心脏缺陷，这也是与法洛四联症和迪乔治综合征相关的异常的一个子集。在对照心脏和FAK(nk)心脏之间没有观察到增殖或凋亡的显着差异。然而，观察到 FAK(nk) 心脏近端流出道圆锥脊的心肌化减少。有趣的是，与遗传对照相比，分离的 FAK-null 心肌细胞的趋化性显着减弱，并且这些效应伴随着 Crk 相关底物 (CAS) 酪氨酸磷酸化的减少。因此，心室间隔和适当的流出道排列可能至少部分依赖于 FAK 依赖性 CAS 激活以及随后诱导极化肌细胞运动到锥脊中。未来的研究将有必要确定额外的 nkx2-5 衍生谱系对观察到的表型的精确贡献。
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.