Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking.
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.
Metzler
Martina
M
Centre for Molecular Medicine and Therapeutics, Childrens and Womens Hospital, Department of Medical Genetics, University of British Columbia, Vancouver, BC, V5Z 4H4.
Li
Bo
B
Gan
Lu
L
Georgiou
John
J
Gutekunst
Claire-Anne
CA
Wang
Yushan
Y
Torre
Enrique
E
Devon
Rebecca S
RS
Oh
Rosemary
R
Legendre-Guillemin
Valerie
V
Rich
Mark
M
Alvarez
Christine
C
Gertsenstein
Marina
M
McPherson
Peter S
PS
Nagy
Andras
A
Wang
Yu Tian
YT
Roder
John C
JC
Raymond
Lynn A
LA
Hayden
Michael R
MR
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
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