HYALURONAN IN LIMB MORPHOGENESIS

其目的是阐明细胞外基质和细胞表面的功能 大分子透明质酸（HA）在脊椎动物肢体形态发生中的作用。HA是一种巨大的线性糖胺聚糖，其占据广泛的分子结构域并具有显著的水化能力。HA在多种模型系统中促进细胞的迁移和增殖，并且HA与其细胞表面受体（包括CD44）的结合也可以激活细胞内信号传导。HA最近被认为是EGFR/ErbB信号网络的共刺激分子，EGFR/ErbB信号网络是涉及肢体形态发生和模式化的信号通路。发育中的肢芽的远端亚根尖间充质细胞， 响应于顶端外胚层嵴（AER）和其他信号传导中心的增殖和图案化产生大量HA，其在细胞之间形成膨胀的水合细胞外基质。因此，细胞和组织的相互作用控制的生长和图案的肢体发生在一个环境中丰富的细胞外和细胞周HA。基于其在许多其他系统中刺激增殖、迁移和细胞内信号传导的作用，将研究HA促进根尖下间充质细胞响应AER的增殖和定向迁移的假设，以及HA调节一种或多种信号传导途径，特别是调节根尖下中胚层肢体图案形成事件的EGFR/ErbB信号传导网络的假设。当肢芽中央核心的间充质细胞位于AER信号传导范围之外时， HA产量下降到低水平，细胞外HA被去除。假设这个 将研究HA合成的下调和细胞外HA的去除对于细胞形成触发软骨形成分化的前软骨凝聚是必需的。HA也通过AER以相对高的量合成。HA分泌的AER可能发挥重要作用，促进AER亚嵴中胚层相互作用，导致定向肢体生长的假设将进行调查。

The goal of this is to elucidate the functions of the extracellular matrix and cell surface macromolecule hyaluronan (HA) in vertebrate limb morphogenesis. HA is a huge linear glycosaminoglycan which occupies an extensive molecular domain and has a pronounced hydration capacity. HA promotes the migration and proliferation of cells in a variety of model systems, and the binding of HA to its cell surface receptors including CD44 can also activate intracellular signaling. HA has recently been implicated as a costimulator of the EGFR/ErbB signaling network, which is a signaling pathway involved limb morphogenesis and patterning. The distal subapical mesenchymal cells of the developing limb bud, which are undergoing proliferation and patterning in response to the apical ectodermal ridge (AER) and other signaling centers, produce high amounts of HA which forms an expansive hydrated extracellular matrix between the cells. Thus, the cell and tissue interactions controlling the outgrowth and patterning of the limb occur in an environment rich in extracellular and pericellular HA. Based on its role in stimulating proliferation, migration, and intracellular signaling in many other systems, the hypothesis that HA facilitates the proliferation and directed migration of the subapical mesenchymal cells in response to the AER will be investigated, as will the hypothesis that HA modulates one or more of the signaling pathways particularly the EGFR/ErbB signaling network that regulates limb patterning events in the subapical mesoderm. As the mesenchymal cells in the central core of the limb bud become located outside of the range of AER signaling, HA production declines to low levels and extracellular HA is removed. The hypothesis that this downregulation of HA synthesis and removal of extracellular HA is necessary for the cells to form the precartilage condensations that trigger chondrogenic differentiation will be investigated. HA is also synthesized in relatively high amounts by the AER. The hypothesis that HA secreted by the AER may play an important role in facilitating the AER-subridge mesoderm interactions that result in directed limb outgrowth will be investigated.