Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1
Degenerative phenotypes caused by the combined deficiency of murine HIP1 and HIP1r are rescued by human HIP1
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DOI：
10.1093/hmg/ddm076
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发表时间：
2007-06-01
影响因子：
3.5
通讯作者：
Ross, Theodora S.
中科院分区：
文献类型：
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作者：
Bradley, Sarah V.;Hyun, Teresa S.;Ross, Theodora S.
亨廷顿蛋白相互作用蛋白-1（HIP 1）家族的成员HIP 1和HIP 1相关（HIP 1 r）是与肌醇脂质、网格蛋白和肌动蛋白相互作用的多结构域蛋白。HIP 1在多种癌症中过度表达，HIP 1和HIP 1 r都延长了多种生长因子受体的半衰期。为了更好地了解HIP 1家族在体内的生理重要性，我们分析了一大群双Hip 1/Hip 1 r敲除（DKO）小鼠。所有DKO小鼠都是侏儒，患有严重的脊椎缺陷，并在成年早期死亡。这些表型在成年早期的单一Hip 1或Hip 1 r敲除中没有观察到，表明HIP 1和HIP 1 r相互补偿。尽管HIP 1和HIP 1 r在过表达时能够调节生长因子受体水平，但本文使用DKO成纤维细胞的研究表明，HIP 1家族对于内吞作用不是必需的，但对于体内维持多种成体组织是必需的。为了测试人HIP 1是否可以与小鼠HIP 1类似地起作用，产生了具有人HIP 1 cDNA的“普遍存在的”表达的转基因小鼠，并与DKO小鼠杂交。引人注目的是，复合人HIP 1转基因DKO小鼠完全没有侏儒症和脊柱缺陷。这一成功的拯救表明，人类HIP 1蛋白在体内与HIP 1和HIP 1 r共享一些可互换的功能。此外，我们的结论是，在DKO小鼠中看到的退行性表型主要是由于HIP 1和HIP 1 r蛋白缺乏，而不是改变相邻基因的表达或破坏内含子元件。
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.