Pdlim7 is required for maintenance of the mesenchymal/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development.
Pdlim7 is required for maintenance of the mesenchymal/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development.
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DOI：
10.1186/1471-213x-10-104
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发表时间：
2010-10-15
影响因子：
--
通讯作者：
Simon HG
中科院分区：
文献类型：
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作者：
Camarata T;Snyder D;Schwend T;Klosowiak J;Holtrup B;Simon HG
脊椎动物肢体发育涉及肢体间充质和上覆的顶端外胚层嵴（AER）之间的相互反馈回路。几种基因通路参与这个反馈回路，包括Fgf信号传导。在前肢外侧板间充质中，Tbx5激活Fgf10表达，这反过来又启动和维持间充质/AER Fgf信号环。最近的研究发现，Tbx5的转录活性受到动态核质穿梭和与PDZ-LIM蛋白家族成员Pdlim 7沿沿着肌动蛋白丝相互作用的调节。这种Tbx5调节在心脏形成中至关重要，但这两种蛋白在其他发育组织中的共表达表明了更广泛的功能作用。Pdlim 7功能的敲低导致胸鳍细胞增殖减少，导致严重发育不良的鳍表型。虽然早期的基因诱导和图案在假定的鳍领域似乎正常，胸鳍前体细胞显示压缩和迁移缺陷之间的18和24小时受精（hpf）。在鳍生长期间，fgf24依次在间充质中表达，然后在顶端外胚层嵴（AER）中表达。然而，在pdlim7反义吗啉代处理的胚胎中，这种表达的转换被阻止，并且fgf24在间充质细胞中保持异位活性。沿着AER中fgf 24的缺乏，包括fgf 8在内的其他关键因子减少，表明潜在间充质的信号传导问题。由于在Pdlim 7不存在的情况下AER功能受到干扰，鳍间充质中的途径组分被错误调节或不存在，表明FGF信号传导反馈环的破坏，这最终导致鳍长出的损失。这项工作为Pdlim 7参与胸鳍发育提供了第一个证据。适当的鳍生长需要fgf24下调的鳍间充质与随后的激活AER，和Pdlim 7似乎调节这种转变，可能通过Tbx5的调节。通过控制Tbx5亚细胞定位和转录活性以及可能的其他未知手段，Pdlim 7是心脏和鳍的正常发育所必需的。这些新的调节机制可能对我们如何解释Tbx5在人类先天性手/心脏综合征中的功能具有重要意义。
Vertebrate limb development involves a reciprocal feedback loop between limb mesenchyme and the overlying apical ectodermal ridge (AER). Several gene pathways participate in this feedback loop, including Fgf signaling. In the forelimb lateral plate mesenchyme, Tbx5 activates Fgf10 expression, which in turn initiates and maintains the mesenchyme/AER Fgf signaling loop. Recent findings have revealed that Tbx5 transcriptional activity is regulated by dynamic nucleocytoplasmic shuttling and interaction with Pdlim7, a PDZ-LIM protein family member, along actin filaments. This Tbx5 regulation is critical in heart formation, but the coexpression of both proteins in other developing tissues suggests a broader functional role. Knock-down of Pdlim7 function leads to decreased pectoral fin cell proliferation resulting in a severely stunted fin phenotype. While early gene induction and patterning in the presumptive fin field appear normal, the pectoral fin precursor cells display compaction and migration defects between 18 and 24 hours post-fertilization (hpf). During fin growth fgf24 is sequentially expressed in the mesenchyme and then in the apical ectodermal ridge (AER). However, in pdlim7 antisense morpholino-treated embryos this switch of expression is prevented and fgf24 remains ectopically active in the mesenchymal cells. Along with the lack of fgf24 in the AER, other critical factors including fgf8 are reduced, suggesting signaling problems to the underlying mesenchyme. As a consequence of perturbed AER function in the absence of Pdlim7, pathway components in the fin mesenchyme are misregulated or absent, indicating a breakdown of the Fgf signaling feedback loop, which is ultimately responsible for the loss of fin outgrowth. This work provides the first evidence for the involvement of Pdlim7 in pectoral fin development. Proper fin outgrowth requires fgf24 downregulation in the fin mesenchyme with subsequent activation in the AER, and Pdlim7 appears to regulate this transition, potentially through Tbx5 regulation. By controlling Tbx5 subcellular localization and transcriptional activity and possibly additional yet unknown means, Pdlim7 is required for proper development of the heart and the fins. These new regulatory mechanisms may have important implications how we interpret Tbx5 function in congenital hand/heart syndromes in humans.