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The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain

Molecular Psychiatry volume 21, pages 925–935 (2016)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by National Institute of Mental Health (NIMH), grants K99MH087628 and R00MH087628, and Institute for Mental Health Research grant to SQ. We thank Dr Daping Fan (University of South Carolina) for his expert guidance in RNAi constructs.

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  1. Y Peng and Z Lu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA

    Y Peng, Z Lu, G Li, M Piechowicz, M Anderson, Y Uddin & S Qiu

  2. Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China

    Z Lu

  3. Interdisciplinary Graduate Program in Neuroscience, School of Life Science, Arizona State University, Tempe, AZ, USA

    G Li & S Qiu

  4. Division of Neurology, Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, USA

    J Wu

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Peng, Y., Lu, Z., Li, G. et al. The autism-associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain. Mol Psychiatry 21, 925–935 (2016). https://doi.org/10.1038/mp.2015.182

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