Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling
Molecular mechanisms underlying limb anomalies associated with cholesterol deficiency during gestation: implications of Hedgehog signaling
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DOI：
10.1093/hmg/ddg129
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发表时间：
2003-05-15
影响因子：
3.5
通讯作者：
Roux, C
中科院分区：
文献类型：
--
作者：
Gofflot, F;Hars, C;Roux, C
由胆固醇生物合成的先天性错误引起的人类疾病的特征在于多个器官的畸形。这包括在某些疾病中高频率观察到的肢体畸形，例如Smith-Lemli-Opitz综合征，表明胆固醇在肢体形态发生中起关键作用。最近，已经证明胆固醇可以调节Hedgehog蛋白的活性，Hedgehog蛋白作为形态发生素来调节许多胚胎结构的精确模式，其中包括发育中的肢体。为了深入了解胆固醇在肢体发育过程中的功能以及Hedgehog信号在肢体缺陷发生中的潜在作用，我们开发了胆固醇缺乏的体内大鼠模型。我们在这里表明，治疗与Triparanol，胆固醇生物合成的远端抑制剂，诱导图案缺陷的autopod在高频率，包括轴前并指和轴后多指，从而再现肢体异常经常观察到人类。使用原位杂交，我们表明，这些畸形起源于修改的音刺猬信号在肢芽在13天后cobaly，导致肢体的前部的不足。这种缺陷导致形成软骨中Indian Hedgehog表达的不平衡，最终导致趾间细胞凋亡和并指畸形减少。因此，我们的研究揭示了啮齿动物中与胆固醇缺乏相关的肢体缺陷发生的分子机制，最有可能是人类。
Human disorders caused by inborn errors of cholesterol biosynthesis are characterized by dysmorphogenesis of multiple organs. This includes limb malformations that are observed at high frequency in some disorders, such as the Smith-Lemli-Opitz syndrome, indicating a pivotal role of cholesterol in limb morphogenesis. Recently, it has been demonstrated that cholesterol can modulate the activity of the Hedgehog proteins, that act as morphogens to regulate the precise patterning of many embryonic structures, among which the developing limbs. To provide insight in the functions of cholesterol during limb development and in the potential role of Hedgehog signaling in the genesis of limb defects, we developed an in vivo rat model of cholesterol deficiency. We show here that treatment with Triparanol, a distal inhibitor of cholesterol biosynthesis, induced patterning defects of the autopod at high frequency, including pre-axial syndactyly and post-axial polydactyly, thus reproducing limb anomalies frequently observed in humans. Using in situ hybridization, we show that these malformations originate from a modification of Sonic Hedgehog signaling in the limb bud at 13 days post-coitum, leading to a deficiency of the anterior part of the limb. This deficiency results in an imbalance of Indian Hedgehog expression in the forming cartilage, ultimately leading to reduced interdigital apoptosis and syndactyly. Our study thus unravels the molecular mechanisms underlying the genesis of limb defects associated with cholesterol deficiency in rodents, and most probably in humans.