LUNATIC FRINGE, SOMITOGENESIS AND SEGMENTATION CLOCKS

在发育过程中，细胞区域内边界的建立可以指导它们未来的生长和模式。 边缘已被证明在果蝇发育过程中这些边界的建立中发挥着重要作用。 哺乳动物的边缘同源物已经被鉴定出来，并且有证据表明它们在脊椎动物的图案形成中发挥着类似的作用。具体而言，Lunatic fringe (Lfng) 已被证明参与体细胞发生过程中发育边界的建立，并进一步被证明与新描述的调节体细胞发生的分段时钟有关。 小鼠转基因将用于功能性鉴定顺式作用调控元件，这些元件控制 Lfng 的精确组织和发育限制表达，并将其表达模式与分段时钟联系起来。 这些区域的定位将有助于在 DNA 水平上识别这些调控元件。 这些调控区域也将在边缘基因家族功能重叠的研究中发挥关键作用，因为它们允许其他家族成员在 Lfng 表达模式中受控异位表达。 边缘蛋白在Notch信号通路的调节中发挥着关键作用，因此这些研究将直接关系到确定该通路在正常发育中的作用和调节。 该通路与多种人类疾病有关，包括癌症、Alagille 综合征和 CADASIL 综合征，通过增加对基础生物学的了解，将加强对这些健康问题的进一步研究。

During development, the establishment of boundaries within fields of cells can direct their future growth and patterning. Fringe has been shown to play an important role in the establishment of these boundaries during Drosophila development. Mammalian homologs of fringe have been identified and evidence suggests that they play a similar role in vertebrate patterning. Specifically, Lunatic fringe (Lfng) has been shown to be involved in establishing developmental boundaries during somitogenesis, and has further been demonstrated to be linked to a newly described segmentation clock that regulates somitogenesis. Mouse transgenesis will be used to functionally identify cis-acting regulatory elements that control the precise tissue and developmentally restricted expression of Lfng, and that tie its expression pattern to a segmentation clock. Localization of these regions will facilitate the identification of these regulatory elements on a DNA level. These regulatory regions will also play a critical role in studies of functional overlap within the fringe gene family by permitting controlled ectopic expression of other family members in the expression pattern of Lfng. Fringe proteins play a key role in the modulation of the Notch signaling pathway, thus these studies will be directly relevant to determining the role and regulation of this pathway in normal development. This pathway has been implicated in several human diseases including cancer, Alagille syndrome and CADASIL syndrome, and the further studies of these health problems will be enhanced by increased knowledge of the underlying biology.