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

Persistent Link:
http://hdl.handle.net/10150/617181
Title:
The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain
Author:
Peng, Yun; Lu, Zhongming; Li, Guohui; Piechowicz, Mariel; Anderson, Miranda; Uddin, Yasin; Wu, Jie; Qiu, Shengfeng
Affiliation:
Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix
Issue Date:
2016-07
Publisher:
NATURE PUBLISHING GROUP
Citation:
Molecular Psychiatry (2016) 21, 925–935; doi:10.1038/mp.2015.182
Journal:
Molecular Psychiatry
Rights:
© 2016 Macmillan Publishers Limited All rights reserved.
Collection Information:
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
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 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.
Note:
Published online 5 January 2016. 6 month embargo.
PubMed ID:
26728565
DOI:
10.1038/mp.2015.182
Version:
Final accepted manuscript
Sponsors:
National Institute of Mental Health (NIMH) [K99MH087628, R00MH087628]; Institute for Mental Health Research.
Additional Links:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914424/

Full metadata record

DC FieldValue Language
dc.contributor.authorPeng, Yunen
dc.contributor.authorLu, Zhongmingen
dc.contributor.authorLi, Guohuien
dc.contributor.authorPiechowicz, Marielen
dc.contributor.authorAnderson, Mirandaen
dc.contributor.authorUddin, Yasinen
dc.contributor.authorWu, Jieen
dc.contributor.authorQiu, Shengfengen
dc.date.accessioned2016-07-19T01:09:40Z-
dc.date.available2016-07-19T01:09:40Z-
dc.date.issued2016-07-
dc.identifier.citationMolecular Psychiatry (2016) 21, 925–935; doi:10.1038/mp.2015.182en
dc.identifier.pmid26728565-
dc.identifier.doi10.1038/mp.2015.182-
dc.identifier.urihttp://hdl.handle.net/10150/617181-
dc.description.abstractThe 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.en
dc.description.sponsorshipNational Institute of Mental Health (NIMH) [K99MH087628, R00MH087628]; Institute for Mental Health Research.en
dc.language.isoenen
dc.publisherNATURE PUBLISHING GROUPen
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914424/en
dc.rights© 2016 Macmillan Publishers Limited All rights reserved.en
dc.titleThe autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrainen
dc.typeArticleen
dc.contributor.departmentDepartment of Basic Medical Sciences, University of Arizona College of Medicine-Phoenixen
dc.identifier.journalMolecular Psychiatryen
dc.description.notePublished online 5 January 2016. 6 month embargo.en
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal accepted manuscripten
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