Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression
Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression
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DOI：
10.1242/dev.02395
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发表时间：
2006-06-01
期刊：
影响因子：
4.6
通讯作者：
Selleri, Licia
中科院分区：
文献类型：
--
作者：
Capellini, Terence D.;Di Giacomo, Giuseppina;Selleri, Licia
脊椎动物的肢体发育沿着三个主轴--近端、前后部和背腹部--通过极化活动区(ZPA)等信号中心的组织建立。而肢体末端的发育又需要在Sonic Hedgehog(Shh)的ZPA表达和顶端外胚层脊之间建立一个分子反馈环。故事中的同源蛋白Pbx1已被证明是近端肢体发育所必需的。在本研究中，我们首先发现Pbx1和Pbx2在侧板和早期肢野中胚层中共同表达。后来，Pbx2在整个肢体中表达，不像Pbx1，它只在近端的芽中表达。通过利用Pbx1/Pbx2功能丧失的小鼠模型，我们证明，尽管Pbx2缺陷(Pbx2(-/-))胚胎中没有肢体异常，但复合Pbx1(-/-)；Pbx2(+/-)突变，除了它们恶化的近端肢体缺陷外，还表现出新的和严重的远端异常。此外，我们还发现Pbx1(-/-)；Pbx2(-/-)胚胎完全没有四肢。此外，我们发现，与果蝇不同的是，在果蝇中，腿独立于HOX发育，并且需要PBX正位同源EXD来指定近端(但不是远端)肢体，而在脊椎动物中，远端肢体模式是依赖于Pbx1/Pbx2的。事实上，我们证明了PBX的遗传需求至少部分是通过它们对Hox空间分布和Shh表达的分级控制来调节的。总之，我们证实，通过控制HOX基因在后肢的空间表达和调节ZPA功能，Pbx1/Pbx2对HOx基因起主要的等级功能，而不仅仅是作为HOx的辅助因子。
Vertebrate limb development occurs along three cardinal axes-proximodistal, anteroposterior and dorsoventral-that are established via the organization of signaling centers, such as the zone of polarizing activity ( ZPA). Distal limb development, in turn, requires a molecular feedback loop between the ZPA expression of sonic hedgehog ( Shh) and the apical ectodermal ridge. The TALE homeoprotein Pbx1 has been shown to be essential for proximal limb development. In this study, we first uncover that Pbx1 and Pbx2 are co-expressed in the lateral plate and early limb field mesoderm. Later, Pbx2 is expressed throughout the limb, unlike Pbx1, which is expressed only in the proximal bud. By exploiting a Pbx1/Pbx2 loss-of-function mouse model, we demonstrate that, despite the lack of limb abnormalities in Pbx2-deficient ( Pbx2(-/-)) embryos, compound Pbx1(-/-); Pbx2(+/-) mutants, in addition to their exacerbated proximal limb defects, exhibit novel and severe distal abnormalities. Additionally, we reveal that Pbx1(-/-); Pbx2(-/-) embryos lack limbs altogether. Furthermore, we establish that, unlike in flies, where the leg develops independently of Hox and where the Pbx ortholog Exd is required for specification of proximal ( but not distal) limbs, in vertebrates, distal limb patterning is Pbx1/Pbx2 dependent. Indeed, we demonstrate that Pbx genetic requirement is mediated, at least in part, through their hierarchical control of Hox spatial distribution and Shh expression. Overall, we establish that, by controlling the spatial expression of Hox genes in the posterior limb and regulating ZPA function, Pbx1/Pbx2 exert a primary hierarchical function on Hox genes, rather than behaving merely as Hox ancillary factors.