The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain.
The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain.
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DOI：
10.1038/mp.2015.182
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发表时间：
2016-07
影响因子：
11
通讯作者：
Qiu S
中科院分区：
文献类型：
--
作者：
Peng Y;Lu Z;Li G;Piechowicz M;Anderson M;Uddin Y;Wu J;Qiu S
人类MET基因赋予自闭症谱系障碍（ASD）的复制风险，并涉及大脑的结构和功能完整性。MET编码受体酪氨酸激酶MET，其在胚胎发生中起多效性作用并修饰大量神经发育事件。然而，关于MET信号如何参与不同的细胞事件以共同影响ASD相关疾病领域的大脑发育，我们知之甚少。在这里，我们表明，MET蛋白的表达是动态调节和区室化的发展中的神经元。MET在早期发育阶段在神经元生长锥中大量表达，并且其激活与小GTdR Cdc42接合以促进神经元生长、树突状分支和棘形成。小鼠背侧腭突中MET信号传导的基因消融导致指示早期功能成熟的神经元形态改变。相反，MET的长期激活抑制了突触的形成和功能成熟。此外，在发育中的前额叶投射神经元中体内操纵MET信号传导水平会破坏这些神经元上的局部回路连接。因此，正常的时间限定的MET信号传导在调节神经元生长、突触能突触成熟和皮质回路功能的时间方面是至关重要的。MET信号转导失调可能导致前脑成熟和连接的病理变化，从而导致与ASD相关的神经症状的出现。
The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which plays a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events. Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect brain development in ASD-relevant disease domains. Here, we show that MET protein expression is dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to promote neuronal growth, dendritic arborization, and spine formation. Genetic ablation of MET signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional maturation. In contrast, prolonged activation of MET represses the formation and functional maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the developing prefrontal projection neurons disrupts the local circuit connectivity made onto these neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the emergence of neurological symptoms associated with ASD.