The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling
The zebrafish iguana locus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling
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DOI：
10.1242/dev.01059
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发表时间：
2004-06-01
期刊：
影响因子：
4.6
通讯作者：
Kawakami, A
中科院分区：
文献类型：
--
作者：
Sekimizu, K;Nishioka, N;Kawakami, A
刺猬(Hedgehog，HH)细胞间信号分子家族的成员在动物发育中起着至关重要的作用。在人类中，HH信号的异常调节会导致发育缺陷，并导致各种遗传疾病和癌症。我们通过对斑马鱼中线突变体鬣蜥(IGU)的分析，鉴定了一种新的HH信号调节因子。IGU的突变导致HH靶基因在腹神经管中表达减少，类似于斑马鱼突变体中已知的影响HH信号的表型。乍一看，IGU突变导致体节中HH靶基因表达扩大，这一点与此相矛盾。遗传学和药理学分析表明，在IGU突变体中，HH靶基因的表达需要Gli激活功能，而不依赖于Smoothens功能。我们的结果表明，在IGU突变体中，无论是在神经管中还是在体节中，Gli蛋白激活HH靶基因表达的能力通常都会降低。尽管HH信号活性的降低导致神经管中HH靶基因表达的丧失，但由于对HH信号的不同阈值反应，同样低水平的HH信号似乎足以激活整个体节中的HH靶基因。我们还表明，在IGU突变体中，HH靶基因的表达对通常抑制HH信号的蛋白激酶A活性的增加具有抵抗力。总之，我们的数据表明，IGU突变既损害了Gli蛋白对HH信号的完全激活，也损害了远离HH来源的组织中对HH信号的负调控。定位克隆显示，IGU基因编码Dzip1，这是一种新的胞内蛋白，含有单一的锌指蛋白-蛋白相互作用结构域。IGU/Dzip1蛋白的过表达提示IGU/Dzip1在HH信号通路中起允许的作用。综上所述，我们的研究表明，IGU/Dzip1作为一个允许因子发挥作用，这是适当调节HH靶基因响应HH信号所必需的。
Members of the Hedgehog (Hh) family of intercellular signaling molecules play crucial roles in animal development. Aberrant regulation of Hh signaling in humans causes developmental defects, and leads to various genetic disorders and cancers. We have characterized a novel regulator of Hh signaling through the analysis of the zebrafish midline mutant iguana (igu). Mutations in igu lead to reduced expression of Hh target genes in the ventral neural tube, similar to the phenotype seen in zebrafish mutants known to affect Hh signaling. Contradictory at first sight, igu mutations lead to expanded Hh target gene expression in somites. Genetic and pharmacological analyses revealed that the expression of Hh target genes in igu mutants requires Gli activator function but does not depend on Smoothened function. Our results show that the ability of Gli proteins to activate Hh target gene expression in response to Hh signals is generally reduced in igu mutants both in the neural tube and in somites. Although this reduced Hh signaling activity leads to a loss of Hh target gene expression in the neural tube, the same low levels of Hh signaling appear to be sufficient to activate Hh target genes throughout somites because of different threshold responses to Hh signals. We also show that Hh target gene expression in igu mutants is resistant to increased protein kinase A activity that normally represses Hh signaling. Together, our data indicate that igu mutations impair both the full activation of Gli proteins in response to Hh signals, and the negative regulation of Hh signaling in tissues more distant from the source of Hh. Positional cloning revealed that the igu locus encodes Dzip1, a novel intracellular protein that contains a single zinc-finger protein-protein interaction domain. Overexpression of Igu/Dzip1 proteins suggested that Igu/Dzip1 functions in a permissive way in the Hh signaling pathway. Taken together, our studies show that Igu/Dzip1 functions as a permissive factor that is required for the proper regulation of Hh target genes in response to Hh signals.