Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration
Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration
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DOI：
10.1242/dev.093526
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发表时间：
2014-03-15
期刊：
影响因子：
4.6
通讯作者：
Guenel, Murat
中科院分区：
文献类型：
--
作者：
Louvi, Angeliki;Nishimura, Sayoko;Guenel, Murat
脑海绵状血管畸形3（CCM 3）功能丧失导致常染色体显性脑血管病。在这里，我们揭示了CCM 3在调节新皮层神经元迁移中的发育作用。在小鼠中使用细胞类型特异性基因失活，我们表明，CCM 3在神经祖细胞中具有细胞自主性和细胞非自主性功能，并且在放射状胶质细胞和通过室管膜下区迁移的新生锥体神经元中特别需要，但在通过皮质板迁移的神经元中不需要。CCM 3功能的丧失导致RhoA激活，肌动蛋白和微管细胞骨架的改变影响神经元形态，以及主要晚生神经元的层状定位异常，表明CCM 3参与放射状胶质依赖性运动，并可能与Cdk 5/RhoA通路相互作用。因此，我们确定了一种新型的神经元迁移细胞质调节因子，并证明其在放射状胶质祖细胞和新生神经元中的失活会导致皮质发育严重畸形。
Loss of function of cerebral cavernous malformation 3 (CCM3) results in an autosomal dominant cerebrovascular disorder. Here, we uncover a developmental role for CCM3 in regulating neuronal migration in the neocortex. Using cell type-specific gene inactivation in mice, we show that CCM3 has both cell autonomous and cell non-autonomous functions in neural progenitors and is specifically required in radial glia and newly born pyramidal neurons migrating through the subventricular zone, but not in those migrating through the cortical plate. Loss of CCM3 function leads to RhoA activation, alterations in the actin and microtubule cytoskeleton affecting neuronal morphology, and abnormalities in laminar positioning of primarily late-born neurons, indicating CCM3 involvement in radial glia-dependent locomotion and possible interaction with the Cdk5/RhoA pathway. Thus, we identify a novel cytoplasmic regulator of neuronal migration and demonstrate that its inactivation in radial glia progenitors and nascent neurons produces severe malformations of cortical development.