A role for the Tubby-like protein 1 in rhodopsin transport.
A role for the Tubby-like protein 1 in rhodopsin transport.
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DOI：
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发表时间：
2001-08
影响因子：
4.4
通讯作者：
S. Hagstrom;M. Adamian;Michael S. Scimeca;B. Pawlyk;Guohua Yue;Tiansen Li
中科院分区：
文献类型：
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作者：
S. Hagstrom;M. Adamian;Michael S. Scimeca;B. Pawlyk;Guohua Yue;Tiansen Li
目的通过研究Tubby样蛋白1（Tubby-like protein 1，TULP 1）基因突变小鼠，验证TULP 1基因功能缺失导致新生视紫红质转运异常的假说，并探讨TULP 1和Tubby基因同源蛋白之间的功能关系。方法采用免疫荧光和植片后免疫电镜技术检测TULP 1和视紫红质在光感受器中的亚细胞定位。通过组织学、视网膜电图（ERG）和免疫荧光显微镜检查携带不同tulp 1/tubby等位基因组合的小鼠。结果TULP 1分布在整个光感受器细胞质中，但被排除在外节和细胞核之外。在tulp 1-/-小鼠中，视紫红质的异位积累发生在早期。在感光器间隙和内节质膜的囊泡配置文件是视紫红质的免疫反应。在tulp 1和tubby基因中无效突变的双纯合子小鼠最初发育感光细胞，并在14天龄时表达一组感光细胞标记。此后，它们的光感受器经历爆发性退化，到出生后第17天达到完全退化。双纯合子的疾病表型比单纯合子严重得多。双杂合子是表型正常的。结论：TULP 1功能的缺失导致新生视紫红质的错误路由。TULP 1可能是将新生视紫红质靶向外节的细胞机制的组分。单突变体和双突变体中的疾病表型的比较表明，TULP 1和Tubby在光感受器中的功能不是可互换的，它们也不形成专性功能复合物。
PURPOSE To test the hypothesis that a lack of Tubby-like protein 1 (TULP1) function causes aberrant transport of nascent rhodopsin and to examine the functional relationship between the homologous proteins TULP1 and Tubby by studying mice carrying combined mutations. METHODS Subcellular localization of TULP1 and rhodopsin in photoreceptors was determined by immunofluorescence and by postembedding immunoelectron microscopy. Mice carrying different tulp1/tubby allele combinations were examined by histology, electroretinograms (ERGs), and immunofluorescence microscopy. RESULTS TULP1 is distributed throughout the photoreceptor cytoplasm but is excluded from the outer segments and the nuclei. In the tulp1-/- mice, ectopic accumulation of rhodopsin occurs at an early age. Both the vesicular profiles in the interphotoreceptor space and the inner segment plasma membranes are immunoreactive for rhodopsin. Mice doubly homozygous for null mutations in the tulp1 and tubby genes initially develop photoreceptors and express a battery of photoreceptor markers at age 14 days. Thereafter their photoreceptors undergo a fulminant degeneration that reaches completion by postnatal day 17. The disease phenotype in the double homozygote is much more severe than either single homozygote. Double heterozygotes are phenotypically normal. CONCLUSIONS A lack of TULP1 function results in misrouting of nascent rhodopsin. TULP1 may be a component of the cellular machinery that targets nascent rhodopsin to the outer segments. Comparison of disease phenotypes in the single and double mutants suggests that TULP1 and Tubby are not functionally interchangeable in photoreceptors nor do they form an obligate functional complex.