Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos
Islet1 regulates establishment of the posterior hindlimb field upstream of the Hand2-Shh morphoregulatory gene network in mouse embryos
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DOI：
10.1242/dev.073056
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发表时间：
2012-05-01
期刊：
影响因子：
4.6
通讯作者：
Kawakami, Yasuhiko
中科院分区：
文献类型：
--
作者：
Itou, Junji;Kawakami, Hiroko;Kawakami, Yasuhiko
在前肢和后肢这两个系列结构的发育过程中，不同的遗传系统如何调控共同的途径，目前还不是很清楚。具体地说，HAND2被证明直接调节Shh，启动其在肢体间充质后缘的表达。虽然Hand2-Shh形态调控系统在前肢和后肢芽中都起作用，但最近的一项分析表明，它的上游调控在前肢和后肢芽中是不同的。在前肢形成区，Hand2的表达需要所有四个Hox9基因的组合；然而，在后肢形成区，什么遗传系统调节Hand2-Shh途径仍然是未知的。通过使用Hoxb6Cre转基因在后肢形成区有条件地灭活Islet1，我们证明了Islet1对于建立Hand2-Shh通路上游的后肢区域而不是前肢区域是必需的。Islet1的失活导致了远端和近端的后部结构的丧失，特别是在后肢。我们发现Hand2在后肢区的表达下调，Shh在后肢芽的表达严重受损。在Hoxb6Cre；Islet1突变的骨盆中，以Shh不依赖的方式形成的近端元件与Pitx1/后肢相比显示出互补的缺陷。这表明Islet1和Pitx1在后肢腰带发育过程中平行发挥作用，这与已知的Tbx5在前肢腰带发育中的要求相反。我们的研究已经确定了Islet1在后肢特定发育中的作用，并揭示了Islet1在两个不同的过程中的功能：调节Hand2-Shh途径的上游和对腰带发育的贡献。
How divergent genetic systems regulate a common pathway during the development of two serial structures, forelimbs and hindlimbs, is not well understood. Specifically, HAND2 has been shown to regulate Shh directly to initiate its expression in the posterior margin of the limb mesenchyme. Although the Hand2-Shh morphoregulatory system operates in both the forelimb and hindlimb bud, a recent analysis suggested that its upstream regulation is different in the forelimb and hindlimb bud. A combination of all four Hox9 genes is required for Hand2 expression in the forelimb-forming region; however, it remains elusive what genetic system regulates the Hand2-Shh pathway in the hindlimb-forming region. By conditional inactivation of Islet1 in the hindlimb-forming region using the Hoxb6Cre transgene, we show that Islet1 is required for establishing the posterior hindlimb field, but not the forelimb field, upstream of the Hand2-Shh pathway. Inactivation of Islet1 caused the loss of posterior structures in the distal and proximal regions, specifically in the hindlimb. We found that Hand2 expression was downregulated in the hindlimb field and that Shh expression was severely impaired in the hindlimb bud. In the Hoxb6Cre; Islet1 mutant pelvis, the proximal element that is formed in a Shh-independent manner, displayed complementary defects in comparison with Pitx1-/hindlimbs. This suggests that Islet1 and Pitx1 function in parallel during girdle development in hindlimbs, which is in contrast with the known requirement for Tbx5 in girdle development in forelimbs. Our studies have identified a role for Islet1 in hindlimb-specific development and have revealed Islet1 functions in two distinct processes: regulation upstream of the Hand2-Shh pathway and contributions to girdle development.