Niewmierzycka Agnieszka, Mills Julia, St-Arnaud Rene, Dedhar Shoukat, Reichardt Louis F
Department of Pathology, University of California, San Francisco, California 94143, USA.
J Neurosci. 2005 Jul 27;25(30):7022-31. doi: 10.1523/JNEUROSCI.1695-05.2005.
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-3beta, 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.
整合素连接激酶（Ilk）是一种支架蛋白和激酶，它将整合素受体与肌动蛋白细胞骨架以及参与细胞黏附、迁移和细胞外基质沉积的信号通路相连。从小鼠胚胎背侧前脑神经上皮中靶向缺失Ilk会导致严重的皮质分层缺陷，类似于鹅卵石样（II型）无脑回畸形。成年突变体的缺陷包括边缘区的神经元侵入、边缘区成分的向下移位、大脑半球融合以及齿状回的扇形化。这些病变与丰富的星形胶质细胞增生以及皮质表面基底膜的广泛破碎有关。在皮质发育过程中，神经元异位与放射状胶质细胞突起的严重紊乱以及Cajal-Retzius细胞的移位有关。当从胚胎神经元中特异性缺失Ilk时，未观察到病变。有趣的是，靶向缺失Ilk对皮质细胞的增殖或存活以及两种Ilk底物Pkb/Akt和Gsk-3β 的磷酸化没有影响，这表明Ilk不通过这些酶调节皮质分层。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发挥作用。这项研究证明了Ilk在皮质分层中的关键作用，并表明与Ilk相关的通路参与了鹅卵石样无脑回畸形的发病机制。
