A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis
A defective response to Hedgehog signaling in disorders of cholesterol biosynthesis
复制标题
DOI：
10.1038/ng1134
复制
发表时间：
2003-04-01
期刊：
影响因子：
30.8
通讯作者：
Beachy, PA
中科院分区：
文献类型：
--
作者：
Cooper, MK;Wassif, CA;Beachy, PA
Smith-Lemli-Opitz综合征（SLOS）、纤维甾醇病和纤维硬结病是由胆固醇生物合成最后阶段的缺陷引起的人类综合征。这些综合征中的许多发育畸形发生在组织和结构中，其胚胎模式依赖于分泌蛋白的Hedgehog（Hh）家族的信号传导。在这里，我们报告说，Hh信号的反应是妥协的突变体细胞从SLOS和Lathosterosis的小鼠模型和正常细胞的胆固醇耗尽。我们发现，细胞固醇水平的降低与对Hh信号的反应性降低相关。这种减弱的反应发生在足以正常自动加工Hh蛋白的固醇水平，这需要胆固醇作为辅因子和共价加合物。我们进一步发现，甾醇消耗影响的Smoothened（Smo），Hh信号转导装置的一个重要组成部分的活动。
Smith-Lemli-Opitz syndrome (SLOS), desmosterolosis and lathosterolosis are human syndromes caused by defects in the final stages of cholesterol biosynthesis. Many of the developmental malformations in these syndromes occur in tissues and structures whose embryonic patterning depends on signaling by the Hedgehog (Hh) family of secreted proteins. Here we report that response to the Hh signal is compromised in mutant cells from mouse models of SLOS and lathosterolosis and in normal cells pharmacologically depleted of sterols. We show that decreasing levels of cellular sterols correlate with diminishing responsiveness to the Hh signal. This diminished response occurs at sterol levels sufficient for normal autoprocessing of Hh protein, which requires cholesterol as cofactor and covalent adduct. We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus.