GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking.
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 GIuR2 (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.
Hoogenraad
Casper C
CC
The Picower Center for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Cambridge, Massachusetts 02139, USA.
Milstein
Aaron D
AD
Ethell
Iryna M
IM
Henkemeyer
Mark
M
Sheng
Morgan
M
D000818:Animals; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000502:physiology*; D006056:Golgi Apparatus / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D016547:Kinesins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D036225:Receptor, EphB1 / Q000378:metabolism*; D036183:Receptor, EphB2 / Q000235:genetics / Q000378:metabolism*; D036223:Receptor, EphB3 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D002352:Carrier Proteins; C491308:Grip1 protein, rat; D007141:Immunoglobulin Fc Fragments; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D036225:Receptor, EphB1; D036183:Receptor, EphB2; D036223:Receptor, EphB3; D016547:Kinesins