The role of cell polarity in vertebrate limb outgrowth

细胞极性在脊椎动物肢体生长中的作用

• 批准号: 7251480
• 负责人: JEFFERY R BARROW
• 金额: $ 7.28万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251480
• 关键词: Actins; Amphibia; Apical Ectodermal Ridge; Behavior; Birth; Cell Polarity; Cell Proliferation; Cell Survival; Cell division; Cells; Chemotactic Factors; Clone Cells; Communities; Congenital Abnormality; Cytoskeleton; Data; Defect; Distal; Elements; Embryo; Excision; Family; Fibroblast Growth Factor; Fishes; Human; In Vitro; Label; Laboratories; Ligands; Limb Bud; Limb Development; Limb structure; Mediating; Medical; Mesenchyme; Mitotic spindle; Modeling; Molecular; Morphogenesis; Mus; Pathway interactions; Pattern; Personal Satisfaction; Play; Relative (related person); Research; Research Personnel; Role; Signal Transduction; Testing; Time; Tissues; Transplantation; cell motility; directional cell; gain of function; insight; interest; member; mutant; research study; two-dimensional

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 investigator's long term objective 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 Wnt/planar cell polarity (PCP) signaling in establishing polarity of the actin cytoskeleton and mitotic spindle 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 by which 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 investigator has collected preliminary data suggesting that AER signals activate the expression of the secreted Wnt ligand, Wnt5a in the limb mesenchyme. In fish and amphibian models, Wnt5a has previously been demonstrated to signal through the Wnt/planar cell polarity (PCP) pathway. Wnt/PCP signaling plays a critical role in establishing cellular polarity which underlies directional cell movements and cell divisions during gastrulation, essential for elongating the embryonic axis. He hypothesizes that Fgf signaling from the AER establishes a gradient of Wnt5a expression in the limb mesenchyme, which then establishes polarity in these cells and in turn directs proximal to distal cell movements and/or cell divisions that result in limb outgrowth. In this application the investigator will test the hypothesis that Fgf and Wnt/PCP signaling are necessary and sufficient for polarization of the actin cytoskeleton or the mitotic spindle. Furthermore he will examine the epistatic relationship between Fgf and Wnt/PCP signaling in regulating cell polarity.

描述（由申请人提供）：肢体异常是一些最常见的出生缺陷，每 1,000 名新生儿中约有 0.7 至 1 人出现肢体异常。 因此，了解负责肢体正常生长和模式的机制引起了医学界的极大兴趣。 研究人员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。 该应用专门研究了成纤维细胞生长因子 (FGF) 和 Wnt/平面细胞极性 (PCP) 信号在建立肢体间充质细胞肌动蛋白细胞骨架和有丝分裂纺锤体极性作为肢体生长基础机制中的作用。 一段时间以来，人们已经知道，沿着脊椎动物胚胎肢芽远端边缘存在的外胚层组织小脊是相邻肢间充质生长所必需的。 最近，已证明分泌性成纤维细胞生长因子 (FGF) 家族的成员在该组织（称为顶端外胚层脊或 AER）中表达，并且对于肢体间质的生长来说是必要且充分的。 虽然 FGF 介导生长的机制尚不清楚，但最近的数据表明，它们是通过充当肢体间质的化学引诱剂而不是作为有丝分裂或细胞存活因子来实现这一点的。 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 信号激活肢体间充质中分泌的 Wnt 配体 Wnt5a 的表达。 在鱼类和两栖动物模型中，Wnt5a 先前已被证明可通过 Wnt/平面细胞极性 (PCP) 途径发出信号。 Wnt/PCP 信号传导在建立细胞极性方面发挥着关键作用，细胞极性是原肠胚形成过程中定向细胞运动和细胞分裂的基础，对于延长胚胎轴至关重要。 他假设来自 AER 的 Fgf 信号在肢体间充质中建立了 Wnt5a 表达梯度，然后在这些细胞中建立极性，进而引导近端细胞运动和/或细胞分裂，从而导致肢体生长。 在此应用中，研究人员将测试以下假设：Fgf 和 Wnt/PCP 信号传导对于肌动蛋白细胞骨架或有丝分裂纺锤体的极化是必要且充分的。 此外，他还将研究 Fgf 和 Wnt/PCP 信号在调节细胞极性方面的上位关系。