Hollway Georgina E, Maule John, Gautier Philippe, Evans Timothy M, Keenan David G, Lohs Claudia, Fischer Danielle, Wicking Carol, Currie Peter D
Muscle Development Laboratory, The Victor Chang Cardiac Research Institute, 384 Victoria Street, Darlinghurst 2010, Sydney, Australia.
Dev Biol. 2006 Jun 1;294(1):104-18. doi: 10.1016/j.ydbio.2006.02.032. Epub 2006 Apr 13.
The Hedgehog family of secreted morphogens specifies the fate of a large number of different cell types within invertebrate and vertebrate embryos, including the muscle cell precursors of the embryonic myotome of zebrafish. Formation of Hedgehog-sensitive muscle fates is disrupted within homozygous zebrafish mutants of the "you"-type class, the majority of which disrupt components of the Hedgehog (HH) signal transduction pathway. We have undertaken a phenotypic and molecular characterisation of one of these mutants, you, which we show results from mutations within the zebrafish orthologue of the mammalian gene scube2. This gene encodes a member of the Scube family of proteins, which is characterised by several protein motifs including EGF and CUB domains. Epistatic and molecular analyses position Scube2 function upstream of Smoothened (Smoh), the signalling component of the HH receptor complex, suggesting that Scube2 may act during HH signal transduction prior to, or during, receipt of the HH signal at the plasma membrane. In support of this model we show that scube2 has homology to cubilin, which encodes an endocytic receptor involved in protein trafficking suggesting a possible mode of function for Scube2 during HH signal transduction.
分泌型形态发生素的刺猬家族决定了无脊椎动物和脊椎动物胚胎内大量不同细胞类型的命运，包括斑马鱼胚胎肌节的肌肉细胞前体。在“you”型纯合斑马鱼突变体中，对刺猬信号敏感的肌肉命运形成受到破坏，其中大多数突变体破坏了刺猬（HH）信号转导途径的组成部分。我们对其中一个突变体you进行了表型和分子特征分析，结果表明该突变体是由哺乳动物基因scube2在斑马鱼中的同源基因发生突变所致。该基因编码Scube家族的一种蛋白质成员，其特征是具有包括EGF和CUB结构域在内的几种蛋白质基序。上位性和分子分析表明，Scube2的功能位于HH受体复合物的信号成分Smoothened（Smoh）的上游，这表明Scube2可能在HH信号转导过程中，在质膜接收HH信号之前或期间发挥作用。为支持这一模型，我们表明scube2与cubilin具有同源性，cubilin编码一种参与蛋白质运输的内吞受体，这提示了Scube2在HH信号转导过程中可能的功能模式。
