Peng Y, Lu Z, Li G, Piechowicz M, Anderson M, Uddin Y, Wu J, Qiu S
Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China.
Mol Psychiatry. 2016 Jul;21(7):925-35. doi: 10.1038/mp.2015.182. Epub 2016 Jan 5.
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 has 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.
人类MET基因赋予自闭症谱系障碍（ASD）一种重复的风险，并与大脑的结构和功能完整性有关。MET编码一种受体酪氨酸激酶MET，它在胚胎发生中具有多效性作用，并影响大量神经发育事件。然而，关于MET信号如何参与不同的细胞事件，从而在与ASD相关的疾病领域共同影响大脑发育，我们知之甚少。在这里，我们表明MET蛋白表达在发育中的神经元中受到动态调节并呈区域化分布。MET在发育早期的神经元生长锥中大量表达，其激活作用于小GTP酶Cdc42，以促进神经元生长、树突分支和棘突形成。小鼠背侧皮层中MET信号的基因消融导致神经元形态改变，这表明早期功能成熟出现异常。相反，MET的长期激活会抑制谷氨酸能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体内操纵MET信号水平会破坏作用于这些神经元的局部回路连接。因此，正常的限时MET信号对于调节神经元生长、谷氨酸能突触成熟和皮质回路功能的时机至关重要。MET信号失调可能导致前脑成熟和连接的病理变化，从而导致与ASD相关的神经症状出现。
