α1ACT Is Essential for Survival and Early Cerebellar Programming in a Critical Neonatal Window
α1ACT Is Essential for Survival and Early Cerebellar Programming in a Critical Neonatal Window
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DOI：
10.1016/j.neuron.2019.02.036
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发表时间：
2019-05-22
期刊：
影响因子：
16.2
通讯作者：
Gomez, Christopher M.
中科院分区：
文献类型：
--
作者：
Du, Xiaofei;Wei, Cenfu;Gomez, Christopher M.
出生后小脑的发育是一个精确调控的过程，涉及精心策划的神经基因的表达。与CACNA1A基因缺陷相关的神经系统表型已越来越多地被认识到，但这种关联的分子原理仍然难以捉摸。通过表征剂量依赖性CACNA1A基因缺陷小鼠模型，我们发现α 1ACT作为CACNA1A mRNA的转录因子和二级蛋白，驱动小脑浦肯野细胞内的动态基因表达网络，对新生儿存活是必不可少的。围产期α 1ACT丢失通过神经发生和突触调节网络的破坏导致运动功能障碍。然而，在成年期消除它对小脑的影响很小。这些发现揭示了α 1ACT在促进小鼠和人类神经元发育中的关键作用，并支持钙通道相关小脑疾病基因治疗的基本原理。最后，我们表明，双顺反子表达可能是共同的电压门控钙通道（VGCC）基因家族，并可能有助于解释复杂的遗传综合征。
Postnatal cerebellar development is a precisely regulated process involving well-orchestrated expression of neural genes. Neurological phenotypes associated with CACNA1A gene defects have been increasingly recognized, yet the molecular principles underlying this association remain elusive. By characterizing a dose-dependent CACNA1A gene deficiency mouse model, we discovered that alpha 1ACT, as a transcription factor and secondary protein of CACNA1A mRNA, drives dynamic gene expression networks within cerebellar Purkinje cells and is indispensable for neonatal survival. Perinatal loss of alpha 1ACT leads to motor dysfunction through disruption of neurogenesis and synaptic regulatory networks. However, its elimination in adulthood has minimal effect on the cerebellum. These findings shed light on the critical role of alpha 1ACT in facilitating neuronal development in both mice and humans and support a rationale for gene therapies for calcium-channel-associated cerebellar disorders. Finally, we show that bicistronic expression may be common to the voltage-gated calcium channel (VGCC) gene family and may help explain complex genetic syndromes.