title: Hip1-related mutant mice grow and develop normally but have accelerated spinal abnormalities and dwarfism in the absence of HIP1.
abstract: In mice and humans, there are two known members of the Huntingtin interacting protein 1 (HIP1) family, HIP1 and HIP1-related (HIP1r). Based on structural and functional data, these proteins participate in the clathrin trafficking network. The inactivation of Hip1 in mice leads to spinal, hematopoietic, and testicular defects. To investigate the biological function of HIP1r, we generated a Hip1r mutant allele in mice. Hip1r homozygous mutant mice are viable and fertile without obvious morphological abnormalities. In addition, embryonic fibroblasts derived from these mice do not have gross abnormalities in survival, proliferation, or clathrin trafficking pathways. Altogether, this demonstrates that HIP1r is not necessary for normal development of the embryo or for normal adulthood and suggests that HIP1 or other functionally related members of the clathrin trafficking network can compensate for HIP1r absence. To test the latter, we generated mice deficient in both HIP1 and HIP1r. These mice have accelerated development of abnormalities seen in Hip1 -deficient mice, including kypholordosis and growth defects. The severity of the Hip1r/Hip1 double-knockout phenotype compared to the Hip1 knockout indicates that HIP1r partially compensates for HIP1 function in the absence of HIP1 expression, providing strong evidence that HIP1 and HIP1r have overlapping roles in vivo.
authors.affiliation: Department of Internal Medicine, and Graduate Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Hyun
authors.forename: Lina
authors.initials: L
authors.lastname: Li
authors.forename: Katherine I
authors.initials: KI
authors.lastname: Oravecz-Wilson
authors.forename: Sarah V
authors.initials: SV
authors.lastname: Bradley
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Provot
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Munaco
authors.forename: Ikuko F
authors.initials: IF
authors.lastname: Mizukami
authors.forename: Hanshi
authors.initials: H
authors.lastname: Sun
authors.forename: Theodora S
authors.initials: TS
authors.lastname: Ross
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics* / Q000473:pathology; D004705:Endocytosis / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics*; D010641:Phenotype; D011247:Pregnancy; D013131:Spine / Q000002:abnormalities*; D014018:Tissue Distribution; D033921:Vesicular Transport Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C073368:HIP1 protein, human; C489537:HIP1R protein, human; C489536:Hip1 protein, mouse; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D004247:DNA; D066246:ErbB Receptors