Human Molecular Genetics Advance Access originally published online on April 23, 2007
Human Molecular Genetics 2007 16(11):1279-1292; doi:10.1093/hmg/ddm076
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Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1
1 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-0942, USA, 2 Department of Orthopaedic Surgery, 3 Department of Dermatology and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA, 4 Institute of Molecular Medicine, Peking University, Beijing 100871, China, 5 Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3202, USA and 6 National Hormone and Peptide Program, Harbor-UCLA Medical Center, Torrance, CA 90509, USA
* To whom correspondence should be addressed at: 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA. Tel: +1 7346155509; Fax: +1 7346153947; Email: tsross{at}umich.edu
Received February 3, 2007; Accepted March 20, 2007
The members of the huntingtin-interacting protein-1 (HIP1) family, HIP1 and HIP1-related (HIP1r), are multi-domain proteins that interact with inositol lipids, clathrin and actin. HIP1 is over-expressed in a variety of cancers and both HIP1 and HIP1r prolong the half-life of multiple growth factor receptors. To better understand the physiological importance of the HIP1 family in vivo, we have analyzed a large cohort of double Hip1/Hip1r knockout (DKO) mice. All DKO mice were dwarfed, afflicted with severe vertebral defects and died in early adulthood. These phenotypes were not observed during early adulthood in the single Hip1 or Hip1r knockouts, indicating that HIP1 and HIP1r compensate for one another. Despite the ability of HIP1 and HIP1r to modulate growth factor receptor levels when over-expressed, studies herein using DKO fibroblasts indicate that the HIP1 family is not necessary for endocytosis but is necessary for the maintenance of diverse adult tissues in vivo. To test if human HIP1 can function similar to mouse HIP1, transgenic mice with ‘ubiquitous’ expression of the human HIP1 cDNA were generated and crossed with DKO mice. Strikingly, the compound human HIP1 transgenic DKO mice were completely free from dwarfism and spinal defects. This successful rescue demonstrates that the human HIP1 protein shares some interchangeable functions with both HIP1 and HIP1r in vivo. In addition, we conclude that the degenerative phenotypes seen in the DKO mice are due mainly to HIP1 and HIP1r protein deficiency rather than altered expression of neighboring genes or disrupted intronic elements.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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