Hedgehog-mediated regulation of cell adhesion

动物发育中的组织图案化需要促进和维持 不同细胞群体的物理隔离。许多旁分泌形态原信号已被提出 具体说明细胞亲和力的差异以及尖锐而稳定的边界的形成，这反过来又有助于 在组织生长过程中保持形态组织者的位置和形状。的长期目标是 这个项目是为了了解Hedgehog(HH)信号定义的细胞和分子机制 特定的细胞亲和力并导致HH分泌(无反应)细胞和HH反应细胞的分离 (不分泌)细胞。越来越多的证据表明，某些人类癌细胞分泌的HH可能发出信号 并促进肿瘤的生长和转移。此外，恶性侵袭可能是 被认为是一种正常的细胞分离过程，在这种过程中，癌细胞之间存在交叉粘连 细胞和组织细胞。因此，这项研究不仅将大大有助于我们对 组织构型的分子和细胞基础以及对HH信号通路的进一步了解，本身， 但也将阐明癌症进展的机制，可能导致新的发现 癌症的治疗靶点。 果蝇翅膀形象盘分为前(A)室和后(P)室。P 细胞分泌HH，同时对HH信号不敏感。相比之下，A细胞可以接收和 回答HH，但不要自己表达HH。两个隔间的单元格不混合。 在开发过程中。然而，不能响应HH信号的A细胞不再与P细胞分离。 目前的观点是，对HH信号的响应导致了粘附性的变化，这 差异导致A细胞和P细胞的分离。将该模型遗传系统与BREADS相结合 融合了强大的生物化学、分子和细胞技术的实验方法，我建议： 1)研究HH信号如何直接改变HH分泌的P细胞和HH-1细胞之间的亲和力差异。 通过调节Ihog家族蛋白的细胞表面水平来响应A细胞。2)识别附加单元 参与调节A/P细胞分离的黏附分子。3)调查Shh是否以及如何 信号通过调节脊椎动物Ihog同源物的表达水平来改变细胞亲和力。

Tissue patterning in animal development requires adhesive mechanisms that promote and maintain physical segregation of different cell populations. Many paracrine morphogen signals have been proposed to specify the differences in cell affinity and the formation of sharp and stable boundaries which, in turn, serve to maintain the position and shape of morphogen organizers during the growth of a tissue. The long-term goal of this project is to understand the cellular and molecular mechanisms by which the Hedgehog (Hh) signal defines specific cell affinities and lead to the segregation of Hh-secreting (non-responding) cells and Hh-responding (non-secreting) cells. Increasing evidence indicates that Hh secreted by certain human cancer cells may signal to surrounding tissue and promote tumor growth and metastasis. Furthermore, malignant invasion might be considered a normal process of cell segregation in reverse, in which there is cross-adhesion between cancer cells and tissue cells. Therefore, this study will not only contribute significantly to our knowledge of the molecular and cellular bases of tissue patterning and further understanding of the Hh signal pathway, per se, but will also shed light on the mechanisms of cancer progression, perhaps leading to the discovery of new therapeutic targets in cancers. The Drosophila wing imaginal disc is subdivided into an anterior (A) and a posterior (P) compartment. P cells secrete Hh and, at the same time, are refractory to the Hh signal. In contrast, A cells can receive and respond to Hh, but do not express Hh by themselves. The cells of the two compartments do not intermingle during development. However, A cells unable to respond to the Hh signal no longer segregate from P cells. The current view is that the response to the Hh signal induces a change in the adhesiveness and that this difference leads to the segregation of A cells from P cell. Combining this model genetic system with broad experimental approaches that incorporate powerful biochemical, molecular and cellular techniques, I propose: 1) To investigate how the Hh signal directly alters the affinity differences between Hh-secreting P cells and Hh- responding A cells by modulating cell surface levels of the Ihog family proteins. 2) To identify additional cell adhesion molecules involved in regulating A/P cell segregation. 3) To investigate whether and how the Shh signal alters cell affinity by regulating expression levels of the vertebrate Ihog homologues.