title: Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking.
abstract: Huntingtin interacting protein 1 (HIP1) is a recently identified component of clathrin-coated vesicles that plays a role in clathrin-mediated endocytosis. To explore the normal function of HIP1 in vivo, we created mice with targeted mutation in the HIP1 gene (HIP1(-/-)). HIP1(-/-) mice develop a neurological phenotype by 3 months of age manifest with a failure to thrive, tremor and a gait ataxia secondary to a rigid thoracolumbar kyphosis accompanied by decreased assembly of endocytic protein complexes on liposomal membranes. In primary hippocampal neurons, HIP1 colocalizes with GluR1-containing AMPA receptors and becomes concentrated in cell bodies following AMPA stimulation. Moreover, a profound dose-dependent defect in clathrin-mediated internalization of GluR1-containing AMPA receptors was observed in neurons from HIP1(-/-) mice. Together, these data provide strong evidence that HIP1 regulates AMPA receptor trafficking in the central nervous system through its function in clathrin-mediated endocytosis.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Childrens and Womens Hospital, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 4H4.
authors.forename: Martina
authors.initials: M
authors.lastname: Metzler
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: John
authors.initials: J
authors.lastname: Georgiou
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Gutekunst
authors.forename: Yushan
authors.initials: Y
authors.lastname: Wang
authors.forename: Enrique
authors.initials: E
authors.lastname: Torre
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Devon
authors.forename: Rosemary
authors.initials: R
authors.lastname: Oh
authors.forename: Valerie
authors.initials: V
authors.lastname: Legendre-Guillemin
authors.forename: Mark
authors.initials: M
authors.lastname: Rich
authors.forename: Christine
authors.initials: C
authors.lastname: Alvarez
authors.forename: Marina
authors.initials: M
authors.lastname: Gertsenstein
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Yu Tian
authors.initials: YT
authors.lastname: Wang
authors.forename: John C
authors.initials: JC
authors.lastname: Roder
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002966:Clathrin / Q000378:metabolism; D003124:Colorimetry; D004268:DNA-Binding Proteins; D004705:Endocytosis; D005260:Female; D005455:Fluorescent Antibody Technique; D051379:Mice; D010641:Phenotype; D011247:Pregnancy; D021381:Protein Transport; D018091:Receptors, AMPA / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D002966:Clathrin; D004268:DNA-Binding Proteins; C489536:Hip1 protein, mouse; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid