University Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, 38000 Grenoble, France; INSERM, U1216, 38000 Grenoble, France.
University Grenoble Alpes, Grenoble Institut des Neurosciences, GIN, 38000 Grenoble, France; INSERM, U1216, 38000 Grenoble, France.
Neuron. 2017 Jan 4;93(1):99-114. doi: 10.1016/j.neuron.2016.11.035. Epub 2016 Dec 22.
In the developing cortex, projection neurons undergo multipolar-bipolar transition, radial-directed migration, and maturation. The contribution of these developmental steps to the structure of the adult cortex is not completely understood. Here, we report that huntingtin (HTT), the protein mutated in Huntington's disease, is enriched in polarizing projection neurons. The depletion of HTT in postmitotic projection neurons leads to the mislocalization of layer-specific neuronal populations in the mouse neocortex. HTT is required for the multipolar-bipolar transition of projection neurons and for the maintenance of their bipolar shape during their radial migration. HTT mediates these effects in vivo through the regulation of RAB11-dependent N-Cadherin trafficking. Importantly, HD pathological HTT alters RAB11-dependent neuronal migration. Finally, we show that the cortical defects resulting from the postmitotic loss of HTT specifically during embryonic development affect neuronal morphology at adulthood. Our data reveal a new HTT-RAB11-N-Cadherin pathway regulating multipolar-bipolar transition with direct implications for mature brain. VIDEO ABSTRACT.
在发育中的皮质中，投射神经元经历多极-双极转变、放射状定向迁移和成熟。这些发育步骤对成年皮质结构的贡献尚不完全清楚。在这里，我们报告亨廷顿病突变蛋白（HTT）在极化投射神经元中富集。在有丝分裂后投射神经元中耗尽 HTT 会导致小鼠新皮层中特定神经元群体的位置错误。HTT 是投射神经元的多极-双极转变所必需的，并且在它们的放射状迁移过程中维持它们的双极形状。HTT 通过调节 RAB11 依赖性 N-钙粘蛋白运输在体内介导这些效应。重要的是，HD 病理性 HTT 改变了 RAB11 依赖性神经元迁移。最后，我们表明，在胚胎发育过程中特定的有丝分裂后 HTT 缺失会影响成年期神经元的形态。我们的数据揭示了一个新的 HTT-RAB11-N-钙粘蛋白通路，该通路调节多极-双极转变，对成熟大脑有直接影响。视频摘要。
