Sp6 and Sp8 Transcription Factors Control AER Formation and Dorsal-Ventral Patterning in Limb Development
Sp6 and Sp8 Transcription Factors Control AER Formation and Dorsal-Ventral Patterning in Limb Development
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DOI：
10.1371/journal.pgen.1004468
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发表时间：
2014-08-01
期刊：
影响因子：
4.5
通讯作者：
Ros, Marian A.
中科院分区：
文献类型：
--
作者：
Haro, Endika;Delgado, Irene;Ros, Marian A.
顶端外胚层脊（AER）的形成和维持对脊椎动物肢体的生长和形态形成至关重要。AER的诱导是一个复杂的过程，它依赖于Fgf、Wnt和Bmp信号通路之间的综合相互作用，这些信号通路在早期肢芽的外胚层内以及外胚层和中胚层之间运作。在肢体发育过程中，转录因子Sp6和Sp8在肢体外胚层和AER中表达。Sp6突变小鼠表现出轻微的并指表型，而Sp8突变小鼠表现出严重的肢体截断。这两个突变体在AER成熟和背腹模式上都表现出缺陷。为了进一步了解Sp6和Sp8在肢体发育中的作用，我们制造了在肢体外胚层缺乏Sp6和Sp8活性的小鼠。值得注意的是，Sp6的消除或显著降低；Sp8基因剂量导致四足畸形；出现初芽，但Fgf8和En1均未被激活。携带Sp8 （Sp6(-/-)）等位基因的突变体；Sp8(+/-))表现为双背趾尖的手足裂畸形表型，可能是由于芽中心的AER不正常且不成熟，以及Wnt7a表达异常扩展到腹外胚层。我们的数据与Sp6和Sp8在肢体外胚中作为Wnt/catenin和Bmp信号不可缺少的介质以剂量依赖的方式协同工作是一致的。我们认为这些因素的功能与近端-远端和背侧-腹侧模式有关。
The formation and maintenance of the apical ectodermal ridge (AER) is critical for the outgrowth and patterning of the vertebrate limb. The induction of the AER is a complex process that relies on integrated interactions among the Fgf, Wnt, and Bmp signaling pathways that operate within the ectoderm and between the ectoderm and the mesoderm of the early limb bud. The transcription factors Sp6 and Sp8 are expressed in the limb ectoderm and AER during limb development. Sp6 mutant mice display a mild syndactyly phenotype while Sp8 mutants exhibit severe limb truncations. Both mutants show defects in AER maturation and in dorsal-ventral patterning. To gain further insights into the role Sp6 and Sp8 play in limb development, we have produced mice lacking both Sp6 and Sp8 activity in the limb ectoderm. Remarkably, the elimination or significant reduction in Sp6; Sp8 gene dosage leads to tetra-amelia; initial budding occurs, but neither Fgf8 nor En1 are activated. Mutants bearing a single functional allele of Sp8 (Sp6(-/-); Sp8(+/-)) exhibit a split-hand/foot malformation phenotype with double dorsal digit tips probably due to an irregular and immature AER that is not maintained in the center of the bud and on the abnormal expansion of Wnt7a expression to the ventral ectoderm. Our data are compatible with Sp6 and Sp8 working together and in a dose-dependent manner as indispensable mediators of Wnt/catenin and Bmp signaling in the limb ectoderm. We suggest that the function of these factors links proximal-distal and dorsal-ventral patterning.