Identification of Sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch
Identification of Sonic hedgehog as a candidate gene responsible for the polydactylous mouse mutant Sasquatch
复制标题
DOI：
10.1016/s0960-9822(99)80022-0
复制
发表时间：
1999-01-28
期刊：
影响因子：
9.2
通讯作者：
Krumlauf, R
中科院分区：
文献类型：
--
作者：
Sharpe, J;Lettice, L;Krumlauf, R
半肢畸形-脱位组的小鼠突变体（Ix、Iu、Ist、Dh、Xt和最近鉴定的Hx、Xpl和Rim4;[1 - 5]）具有共同的轴前多指（趾）畸形和长骨异常。与手指重复有关的是前肢芽发育调节的变化，导致信号成分如Sonic hedgehog（Shh）和成纤维细胞生长因子-4（Fgf4）的异位表达，但对这种失调的分子原因知之甚少。我们产生的转基因插入事件，这组突变体的新成员，大脚野人（SSQ），这破坏了前后（AP）和背腹（DV）图案的方面。该突变体在杂合子胚胎的后肢和纯合子胚胎的后肢和前肢中均表现出轴前多趾。Shh、Fgf4、Fgf8、Hoxd12和Hoxd13基因均异位表达于患肢芽前部。发现插入位点靠近Shh位点。此外，来自转基因报告基因的表达受到调控元件的控制，该调控元件指导反映肢体中Shh的内源性表达模式的模式。在异常的肢体，Shh和报告异位诱导的前部区域，而在正常的肢体的报告和Shh被限制到区的极化活动（ZPA）。这些数据强烈表明，Ssq是由直接干扰Shh基因的顺式调节引起的。
The mouse mutants of the hemimelia-luxate group (Ix, Iu, Ist, Dh, Xt, and the more recently identified Hx, Xpl and Rim4; [1-5]) have in common preaxial polydactyly and longbone abnormalities. Associated with the duplication of digits are changes in the regulation of development of the anterior limb bud resulting in ectopic expression of signalling components such as Sonic hedgehog (Shh) and fibroblast growth factor-4 (Fgf4), but little is known about the molecular causes of this misregulation. We generated, by a transgene insertion event, a new member of this group of mutants, Sasquatch (Ssq), which disrupted aspects of both anteroposterior (AP) and dorsoventral (DV) patterning. The mutant displayed preaxial polydactyly in the hindlimbs of heterozygous embryos, and in both hindlimbs and forelimbs of homozygotes. The Shh, Fgf4, Fgf8, Hoxd12 and Hoxd13 genes were all ectopically expressed in the anterior region of affected limb buds. The insertion site was found to lie close to the Shh locus. Furthermore, expression from the transgene reporter has come under the control of a regulatory element that directs a pattern mirroring the endogenous expression pattern of Shh in limbs. In abnormal limbs, both Shh and the reporter were ectopically induced in the anterior region, whereas in normal limbs the reporter and Shh were restricted to the zone of polarising activity (ZPA). These data strongly suggest that Ssq is caused by direct interference with the cis regulation of the Shh gene.