Some distal limb structures develop in mice lacking Sonic hedgehog signaling
Some distal limb structures develop in mice lacking Sonic hedgehog signaling
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DOI：
10.1016/s0925-4773(00)00492-5
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发表时间：
2001-01-01
影响因子：
2.6
通讯作者：
Loomis, CA
中科院分区：
文献类型：
--
作者：
Kraus, P;Fraidenraich, D;Loomis, CA
肢体的图案化是通过三个信号区的复杂相互作用来协调的：顶端外胚层脊(AER)、极化活动区(ZPA)和非脊肢外胚层。ZPA中的Shh、BMPS与相邻间充质中的拮抗剂、背侧外胚层中的Wnt7a和AER中的FGFs之间存在复杂的反馈环。与之前报道的Shh(-/-)小鼠完全没有手指不同，我们发现Shh(-/-)小鼠的后肢有一个形态上截然不同的手指，指甲和指骨轮廓清晰，中间结构严重截断和融合。远端autopod元件的存在与Hoxd13在Shh(-/-)后肢的弱表达是一致的。相比之下，Shh(-/-)前肢只有一个远端软骨成分，分化较差的指甲和融合的中间骨。有趣的是，IHH在Shh突变肢体的顶端表达，并可能解释远端结构的形成。与以前的研究相反，我们还证明了Shh信号是维持正常Fgf8表达所必需的，因为Fgf8的表达不同于其他一些AER标记基因，在E10.5之后，Fgf8的表达从前到后迅速丧失，只有一小部分Fgf8的表达在后面保留。此外，手板的崩溃与Fgf8表达的丧失是平行的。我们的数据表明，后肢骨骼的大多数中间元素的发育是依赖Shh的，并且Shh信号是双肢AER的前后扩展以及随后的斑足类和自足类元素的分支所必需的。最后，我们证明Shh也是四肢外胚层生长所必需的，从而形成一个不同的四肢隔室。(C)2001爱思唯尔爱尔兰科学有限公司。保留所有权利。
Patterning of the limb is coordinated by the complex interplay of three signaling regions: the apical ectodermal ridge (AER), the zone of polarizing activity (ZPA), and the non-ridge limb ectoderm. Complex feedback loops exist between Shh in the ZPA, Bmps and their antagonists in the adjacent mesenchyme, Wnt7a in the dorsal ectoderm and Fgfs in the AER. In contrast to the previously reported complete absence of digits in Shh(-/-) mice, we show that one morphologically distinct digit, with a well-delineated nail and phalanges, forms in Shh(-/-) hindlimbs, while intermediate structures are severely truncated and fused. The presence of distal autopod elements is consistent with weak expression of Hoxd13 in Shh(-/-) hindlimbs. Shh(-/-) forelimbs in contrast have one distal cartilage element, a less-well differentiated nail and fused intermediate bones. Interestingly, Ihh is expressed at the tip of Shh mutant limbs and could account for formation of distal structures. In contrast to previous studies we also demonstrate that Shh signaling is required for maintenance of normal Fgf8 expression, since expression of Fgf8, unlike some other AER marker genes, is rapidly lost from anterior to posterior after E10.5, with only a small domain of Fgf8 expression remaining posteriorly. Furthermore, loss of expanded Fgf8 expression is paralleled by a collapse of the handplate. Our data show that development of most intermediate elements of the hindlimb skeleton are Shh-dependent, and that Shh signaling is required for anterior-posterior expansion of the AER in both limbs and for the subsequent branching of zeugopod and autopod elements. Finally, we show that Shh is also required for outgrowth of the limb ectoderm and thus for the formation of a distinct limb compartment. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.