GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking

Casper C. Hoogenraad; Aaron D. Milstein; Iryna M. Ethell; Mark Henkemeyer; Morgan Sheng

doi:10.1038/nn1487

GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking

Casper C. Hoogenraad, Aaron D. Milstein, Iryna M. Ethell, Mark Henkemeyer, Morgan Sheng

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183 Scopus citations

Abstract

The function of the multi-PDZ domain scaffold protein GRIP1 (glutamate receptor interacting protein 1) in neurons is unclear. To explore the function of GRIP1 in hippocampal neurons, we used RNA interference (RNAi) to knock down the expression of GRIP1. Knockdown of GRIP1 by small interfering RNA (siRNA) in cultured hippocampal neurons caused a loss of dendrites, associated with mislocalization of the GRIP-interacting proteins GluR2 (AMPA receptor subunit), EphB2 (receptor tyrosine kinase) and KIF5 (also known as kinesin 1; microtubule motor). The loss of dendrites by GRIP1-siRNA was rescued by overexpression of the extracellular domain of EphB2, and was phenocopied by overexpression of the intracellular domain of EphB2 and extracellular application of ephrinB-Fc fusion proteins. Neurons from EphB1-EphB2-EphB3 triple knockout mice showed abnormal dendrite morphogenesis. Disruption of the KIF5-GRIP1 interaction inhibited EphB2 trafficking and strongly impaired dendritic growth. These results indicate an important role for GRIP1 in dendrite morphogenesis by serving as an adaptor protein for kinesin-dependent transport of EphB receptors to dendrites.

Original language	English (US)
Pages (from-to)	906-915
Number of pages	10
Journal	Nature neuroscience
Volume	8
Issue number	7
DOIs	https://doi.org/10.1038/nn1487
State	Published - Jul 25 2005

ASJC Scopus subject areas

General Neuroscience

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title = "GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking",

abstract = "The function of the multi-PDZ domain scaffold protein GRIP1 (glutamate receptor interacting protein 1) in neurons is unclear. To explore the function of GRIP1 in hippocampal neurons, we used RNA interference (RNAi) to knock down the expression of GRIP1. Knockdown of GRIP1 by small interfering RNA (siRNA) in cultured hippocampal neurons caused a loss of dendrites, associated with mislocalization of the GRIP-interacting proteins GluR2 (AMPA receptor subunit), EphB2 (receptor tyrosine kinase) and KIF5 (also known as kinesin 1; microtubule motor). The loss of dendrites by GRIP1-siRNA was rescued by overexpression of the extracellular domain of EphB2, and was phenocopied by overexpression of the intracellular domain of EphB2 and extracellular application of ephrinB-Fc fusion proteins. Neurons from EphB1-EphB2-EphB3 triple knockout mice showed abnormal dendrite morphogenesis. Disruption of the KIF5-GRIP1 interaction inhibited EphB2 trafficking and strongly impaired dendritic growth. These results indicate an important role for GRIP1 in dendrite morphogenesis by serving as an adaptor protein for kinesin-dependent transport of EphB receptors to dendrites.",

author = "Hoogenraad, {Casper C.} and Milstein, {Aaron D.} and Ethell, {Iryna M.} and Mark Henkemeyer and Morgan Sheng",

note = "Funding Information: We thank M. Greenberg for Eph receptor reagents, G. Banker for CD8, A. Hung for GRIP1(L732Y) and A. Akhmanova for pSuper-TRE. C.C.H. is a recipient of a long-term fellowship from Human Frontier Science Program Organization. I.M.E. and M.H. are supported by a National Institute of Mental Health grant and MH66332, respectively. M.S. is an Investigator of the Howard Hughes Medical Institute.",

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AU - Hoogenraad, Casper C.

AU - Milstein, Aaron D.

AU - Ethell, Iryna M.

AU - Henkemeyer, Mark

AU - Sheng, Morgan

N1 - Funding Information: We thank M. Greenberg for Eph receptor reagents, G. Banker for CD8, A. Hung for GRIP1(L732Y) and A. Akhmanova for pSuper-TRE. C.C.H. is a recipient of a long-term fellowship from Human Frontier Science Program Organization. I.M.E. and M.H. are supported by a National Institute of Mental Health grant and MH66332, respectively. M.S. is an Investigator of the Howard Hughes Medical Institute.

PY - 2005/7/25

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N2 - The function of the multi-PDZ domain scaffold protein GRIP1 (glutamate receptor interacting protein 1) in neurons is unclear. To explore the function of GRIP1 in hippocampal neurons, we used RNA interference (RNAi) to knock down the expression of GRIP1. Knockdown of GRIP1 by small interfering RNA (siRNA) in cultured hippocampal neurons caused a loss of dendrites, associated with mislocalization of the GRIP-interacting proteins GluR2 (AMPA receptor subunit), EphB2 (receptor tyrosine kinase) and KIF5 (also known as kinesin 1; microtubule motor). The loss of dendrites by GRIP1-siRNA was rescued by overexpression of the extracellular domain of EphB2, and was phenocopied by overexpression of the intracellular domain of EphB2 and extracellular application of ephrinB-Fc fusion proteins. Neurons from EphB1-EphB2-EphB3 triple knockout mice showed abnormal dendrite morphogenesis. Disruption of the KIF5-GRIP1 interaction inhibited EphB2 trafficking and strongly impaired dendritic growth. These results indicate an important role for GRIP1 in dendrite morphogenesis by serving as an adaptor protein for kinesin-dependent transport of EphB receptors to dendrites.

AB - The function of the multi-PDZ domain scaffold protein GRIP1 (glutamate receptor interacting protein 1) in neurons is unclear. To explore the function of GRIP1 in hippocampal neurons, we used RNA interference (RNAi) to knock down the expression of GRIP1. Knockdown of GRIP1 by small interfering RNA (siRNA) in cultured hippocampal neurons caused a loss of dendrites, associated with mislocalization of the GRIP-interacting proteins GluR2 (AMPA receptor subunit), EphB2 (receptor tyrosine kinase) and KIF5 (also known as kinesin 1; microtubule motor). The loss of dendrites by GRIP1-siRNA was rescued by overexpression of the extracellular domain of EphB2, and was phenocopied by overexpression of the intracellular domain of EphB2 and extracellular application of ephrinB-Fc fusion proteins. Neurons from EphB1-EphB2-EphB3 triple knockout mice showed abnormal dendrite morphogenesis. Disruption of the KIF5-GRIP1 interaction inhibited EphB2 trafficking and strongly impaired dendritic growth. These results indicate an important role for GRIP1 in dendrite morphogenesis by serving as an adaptor protein for kinesin-dependent transport of EphB receptors to dendrites.

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GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking

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