Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh
Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh
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DOI：
10.1242/dev.01115
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发表时间：
2004-05-01
期刊：
影响因子：
4.6
通讯作者：
Mackem, S
中科院分区：
文献类型：
--
作者：
Chen, YT;Knezevic, V;Mackem, S
Sonic hedgehog(Shh)信令同时调节数字和身份，但如何指定不同的不同数字类型(身份)仍不清楚。Shh主要通过阻止GO转录因子裂解成抑制物形式来调节数字的形成，从而关闭Shh靶基因的表达。功能冗余的5‘HOXD基因调节Shh和Go下游的数字模式，通过未知的靶标。在Gli3(+)背景下，几个5‘Hoxd基因中的任何一个的强制表达都会导致不同的不同手指类型的多指畸形，而在Go缺失的肢体中，多指手指都是相似的、短的和畸形的，尽管内源性5’Hoxd基因广泛错误表达。我们发现Hoxd12与Gli3在遗传和物理上相互作用，并可以将GO抑制因子转化为Shh靶基因的激活因子。几个5‘端HOXD基因在肢芽中差异表达，与GO物理上相互作用。我们认为，肢芽上不同的[Gli3]：[Total Hoxd]比率导致GO靶基因的差异激活，并有助于数字模式的调节。由此产生的“有效的”GO激活和抑制功能之间的平衡改变也可能有助于在空间或时间上延长Shh的活动梯度。
Sonic hedgehog (Shh) signaling regulates both digit number and identity, but how different distinct digit types (identities) are specified remains unclear. Shh regulates digit formation largely by preventing cleavage of the GO transcription factor to a repressor form that shuts off expression of Shh target genes. The functionally redundant 5'Hoxd genes regulate digit pattern downstream of Shh and GO, through as yet unknown targets. Enforced expression of any of several 5'Hoxd genes causes polydactyly of different distinct digit types with posterior transformations in a Gli3(+) background, whereas, in GO null limbs, polydactylous digits are all similar, short and dysmorphic, even though endogenous 5'Hoxd genes are broadly misexpressed. We show that Hoxd12 interacts genetically and physically with Gli3, and can convert the GO repressor into an activator of Shh target genes. Several 5'Hoxd genes, expressed differentially across the limb bud, interact physically with GO. We propose that a varying [Gli3]:[total Hoxd] ratio across the limb bud leads to differential activation of GO target genes and contributes to the regulation of digit pattern. The resulting altered balance between 'effective' GO activating and repressing functions may also serve to extend the Shh activity gradient spatially or temporally.