Transient Inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular β-catenin organization and signaling in AER during mouse limb development.
Transient Inhibition of FGFR2b-ligands signaling leads to irreversible loss of cellular β-catenin organization and signaling in AER during mouse limb development.
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DOI：
10.1371/journal.pone.0076248
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Bellusci S
中科院分区：
文献类型：
--
作者：
Danopoulos S;Parsa S;Al Alam D;Tabatabai R;Baptista S;Tiozzo C;Carraro G;Wheeler M;Barreto G;Braun T;Li X;Hajihosseini MK;Bellusci S
脊椎动物的四肢是通过一系列协调的诱导、生长和模式化过程发展起来的。成纤维细胞生长因子受体2b（FGFR 2b）信号传导控制顶端外胚层嵴（AER）的诱导，但其在肢体生长和图案形成以及AER形态和细胞行为中的假定作用仍不清楚。我们已经研究了这些作用，通过分级和可逆表达可溶性显性阴性FGFR 2b分子在不同的时间在小鼠肢体发育，使用强力霉素/反式激活因子/泰特（O）-响应系统。在肢芽诱导之前，E8.5时FGFR 2b配体信号传导的瞬时衰减（≤24小时）主要导致近端骨骼元件的丢失或截短，对远端元件的影响不太严重。然而，从E9.5开始的衰减对AER的稳定性具有不可逆的影响，导致远端肢体骨骼元素的逐渐丧失。FGFR 2b配体衰减的主要后果是细胞粘附的短暂丧失和P63、β1-整联蛋白和E-钙粘蛋白的下调，以及AER内细胞β-连环蛋白组织和WNT信号传导的永久丧失。结合起来，这些作用导致AER细胞在多西环素给药后24小时内从多层细胞逐渐转化为鳞状上皮样细胞。这些发现表明，FGFR 2b配体信号传导在肢体发育期间维持AER中具有关键的阶段特异性作用。
The vertebrate limbs develop through coordinated series of inductive, growth and patterning events. Fibroblast Growth Factor receptor 2b (FGFR2b) signaling controls the induction of the Apical Ectodermal Ridge (AER) but its putative roles in limb outgrowth and patterning, as well as in AER morphology and cell behavior have remained unclear. We have investigated these roles through graded and reversible expression of soluble dominant-negative FGFR2b molecules at various times during mouse limb development, using a doxycycline/transactivator/tet(O)-responsive system. Transient attenuation (≤24 hours) of FGFR2b-ligands signaling at E8.5, prior to limb bud induction, leads mostly to the loss or truncation of proximal skeletal elements with less severe impact on distal elements. Attenuation from E9.5 onwards, however, has an irreversible effect on the stability of the AER, resulting in a progressive loss of distal limb skeletal elements. The primary consequences of FGFR2b-ligands attenuation is a transient loss of cell adhesion and down-regulation of P63, β1-integrin and E-cadherin, and a permanent loss of cellular β-catenin organization and WNT signaling within the AER. Combined, these effects lead to the progressive transformation of the AER cells from pluristratified to squamous epithelial-like cells within 24 hours of doxycycline administration. These findings show that FGFR2b-ligands signaling has critical stage-specific roles in maintaining the AER during limb development.
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