Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin.
Neocortical dendritic complexity is controlled during development by NOMA-GAP-dependent inhibition of Cdc42 and activation of cofilin.
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DOI：
10.1101/gad.191593.112
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发表时间：
2012-08
影响因子：
10.5
通讯作者：
M. Rosário;S. Schuster;R. Jüttner;Srinivas Parthasarathy;V. Tarabykin;W. Birchmeier
中科院分区：
文献类型：
--
作者：
M. Rosário;S. Schuster;R. Jüttner;Srinivas Parthasarathy;V. Tarabykin;W. Birchmeier
新皮层神经元具有高度分支的树突树，这对其功能至关重要。事实上，树突分支的缺陷与人类神经发育障碍有关。然而，调节树突状乔木复杂性的分子机制仍然知之甚少。在这里，我们揭示了皮质发育过程中树突分支调控的分子基础。我们发现，在发展过程中，树突状分支需要有丝分裂后抑制的RhoGTdR Cdc 42。通过产生转基因小鼠，我们证明了这是由新的Cdc 42-GAP NOMA-GAP在体内催化的。NOMA-GAP的丢失导致新皮质体积减少，特别是与皮质树突状树枝化和Cdc 42超活化的深刻过度简化相关。值得注意的是，树突的复杂性和皮质厚度可以部分恢复有丝分裂后Cdc 42水平的遗传减少。此外，我们确定了肌动蛋白调节cofilin作为一个关键的调节树突状细胞的复杂性在体内。后期皮质发育过程中的Cofilin激活依赖于NOMA-GAP表达和随后的Cdc 42抑制。引人注目的是，活性cofilin在子宫内的表达足以恢复NOMA-GAP缺陷动物的出生后树突的复杂性。我们的研究结果定义了一种新的细胞内在机制，以调节树突状分支，从而在大脑皮层神经元的复杂性。
Neocortical neurons have highly branched dendritic trees that are essential for their function. Indeed, defects in dendritic arborization are associated with human neurodevelopmental disorders. The molecular mechanisms regulating dendritic arbor complexity, however, are still poorly understood. Here, we uncover the molecular basis for the regulation of dendritic branching during cortical development. We show that during development, dendritic branching requires post-mitotic suppression of the RhoGTPase Cdc42. By generating genetically modified mice, we demonstrate that this is catalyzed in vivo by the novel Cdc42-GAP NOMA-GAP. Loss of NOMA-GAP leads to decreased neocortical volume, associated specifically with profound oversimplification of cortical dendritic arborization and hyperactivation of Cdc42. Remarkably, dendritic complexity and cortical thickness can be partially restored by genetic reduction of post-mitotic Cdc42 levels. Furthermore, we identify the actin regulator cofilin as a key regulator of dendritic complexity in vivo. Cofilin activation during late cortical development depends on NOMA-GAP expression and subsequent inhibition of Cdc42. Strikingly, in utero expression of active cofilin is sufficient to restore postnatal dendritic complexity in NOMA-GAP-deficient animals. Our findings define a novel cell-intrinsic mechanism to regulate dendritic branching and thus neuronal complexity in the cerebral cortex.