Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly
Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly
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DOI：
10.1523/jneurosci.1695-05.2005
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发表时间：
2005-07-27
影响因子：
5.3
通讯作者：
Reichardt, LF
中科院分区：
文献类型：
--
作者：
Niewmierzycka, A;Mills, J;Reichardt, LF
整合素连接激酶（Ilk）是一种支架和激酶，将整合素受体连接到肌动蛋白细胞骨架和参与细胞粘附、迁移和细胞外基质沉积的信号通路。从胚胎小鼠背前脑神经上皮中靶向删除Ilk可导致严重的皮质层压缺陷，类似于鹅卵石（II型）无脑畸形。成年突变体的缺陷包括边缘区神经元侵入、边缘区成分向下移位、大脑半球融合和齿状回扇形。这些病变与大量的星形胶质细胞增生和皮层表面基底层的广泛碎裂有关。在皮层发育过程中，神经元异位与放射状胶质突的严重紊乱和Cajal- Retzius细胞的移位有关。当从胚胎神经元中特异性地删除Ilk时，不会看到病变。有趣的是，靶向Ilk缺失对皮质细胞的增殖或存活没有影响，也没有影响两种Ilk底物Pkb/Akt和Gsk-3 β的磷酸化，这表明Ilk不通过这些酶调节皮质层压。相反，Ilk在体内作为整合素依赖性基底膜形成的主要细胞内介质。这项研究证明了Ilk在皮质层压中的关键作用，并表明Ilk相关通路参与了鹅卵石状无脑畸形的发病机制。
Integrin- linked kinase ( Ilk) is a scaffold and kinase that links integrin receptors to the actin cytoskeleton and to signaling pathways involved in cell adhesion, migration, and extracellular matrix deposition. Targeted deletion of Ilk from embryonic mouse dorsal forebrain neuroepithelium results in severe cortical lamination defects resembling cobblestone ( type II) lissencephaly. Defects in adult mutants include neuronal invasion of the marginal zone, downward displacement of marginal zone components, fusion of the cerebral hemispheres, and scalloping of the dentate gyrus. These lesions are associated with abundant astrogliosis and widespread fragmentation of the basal lamina at the cortical surface. During cortical development, neuronal ectopias are associated with severe disorganization of radial glial processes and displacement of Cajal- Retzius cells. Lesions are not seen when Ilk is specifically deleted from embryonic neurons. Interestingly, targeted Ilk deletion has no effect on proliferation or survival of cortical cells or on phosphorylation of two Ilk substrates, Pkb/Akt and Gsk-3 beta, suggesting that Ilk does not regulate cortical lamination via these enzymes. Instead, Ilk acts in vivo as a major intracellular mediator of integrin- dependent basal lamina formation. This study demonstrates a critical role for Ilk in cortical lamination and suggests that Ilk- associated pathways are involved in the pathogenesis of cobblestone lissencephalies.