The role of Fgf and Wnt5a signaling in directed outgrowth of the limb mesenchyme

描述（由申请人提供）：肢体异常代表了一些最常见的出生缺陷，发生率约为0.7至1/1000。 因此，了解负责肢体正常生长和形成模式的机制对医学界具有极大的兴趣。 本申请的长期目标是了解驱动肢体生长和形态发生的细胞和分子机制。 本申请具体研究了成纤维细胞生长因子（FGF）和Wnt 5a在调节肢体间充质细胞的定向迁移和定向细胞分裂中的作用，作为肢体生长的基础机制。 一段时间以来，人们已经知道，沿着脊椎动物胚胎肢芽的远端边缘存在的外胚层组织的小脊是相邻肢间充质生长所必需的。 最近，已经证明分泌的成纤维细胞生长因子（FGF）家族的成员在该组织（称为顶端外胚层嵴或AER）中表达，并且对于肢体间充质的生长是必要的和足够的。 虽然FGF介导生长的机制尚不清楚，但最近的数据表明，它们是通过作为肢体间充质的化学引诱物而不是作为促有丝分裂因子或细胞存活因子来实现的。 FGF信号如何介导这种化学吸引？ 研究人员收集的初步数据表明，AER信号激活了肢体间充质中分泌的Wnt配体Wnt 5a的表达。 在脊椎动物和无脊椎动物模型中，Wnt 5a先前已被证明通过Wnt/平面细胞极性（PCP）和/或Ror信号传导途径发出信号，这两者又被证明在体内和体外调节定向细胞运动和细胞分裂。 研究人员假设，来自AER的Fgf信号在肢体间充质中建立了Wnt 5a表达的梯度，然后在这些细胞中建立了细胞极性，并指导近端到远端的细胞运动和/或细胞分裂，导致肢体长出。 在本申请中，他们将测试以下假设：远端肢体中的Fgf和Wnt 5a/Ror信号传导对于肢体间充质细胞的定向迁移和定向细胞分裂都是必要和充分的。 公共卫生相关性：肢体畸形是人类最常见的出生缺陷之一。 本申请中的研究旨在了解正常肢体发育的机制。 预计本文阐明的基本机制将对未来的研究和潜在的治疗方法产生重要影响。

DESCRIPTION (provided by applicant): Limb anomalies represent some of the most common birth defects occurring in approximately 0.7 to 1 per 1,000 human births. Therefore, understanding the mechanisms responsible for the proper outgrowth and patterning of limbs are of great interest to the medical community. The long-term objective of this application is to understand the cellular and molecular mechanisms that drive outgrowth and morphogenesis of the limb. This application specifically examines the role of fibroblast growth factors (FGFs) and Wnt5a in regulating directed migration and oriented cell division of limb mesenchyme cells as mechanisms that underlie limb outgrowth. For some time it has been known that a small ridge of ectodermal tissue that exists along the distal margin of the vertebrate embryonic limb bud is required for outgrowth of the adjacent limb mesenchyme. More recently, it has been demonstrated that members of the secreted fibroblast growth factor (FGF) family are expressed in this tissue (known as the apical ectodermal ridge or AER) and are both necessary and sufficient for outgrowth of the limb mesenchyme. While the mechanisms whereby FGFs mediate outgrowth are unknown, recent data suggest that they do so by acting as a chemoattractant to the limb mesenchyme rather than as a mitogenic or cell survival factor. How does FGF signaling mediate this chemoattraction? The investigators have collected preliminary data suggesting that AER signals activate the expression of the secreted Wnt ligand, Wnt5a, in the limb mesenchyme. In vertebrate and invertebrate models, Wnt5a has previously been demonstrated to signal through the Wnt/planar cell polarity (PCP) and/or Ror signaling pathways, both of which have in turn been shown to regulate directional cell movements and cell divisions in vivo and in vitro. The investigators hypothesize that Fgf signaling from the AER establishes a gradient of Wnt5a expression in the limb mesenchyme which then establishes cellular polarity in these cells and directs proximal to distal cell movements and/or cell divisions that result in limb outgrowth. In this application, they will test the hypotheses that Fgf and Wnt5a/Ror signaling in the distal limb are both necessary and sufficient for directed migration and oriented cell divisions of limb mesenchyme cells. PUBLIC HEALTH RELEVANCE: Limb anomalies are some of the most common birth defects in humans. The research in this application is designed to understand the mechanisms underlying normal limb development. It is anticipated that the basic mechanisms elucidated here will have important implications for future research and potential therapies.