LUNATIC FRINGE, SOMITOGENESIS AND SEGMENTATION CLOCKS

在发育过程中，在细胞领域内建立边界可以指导它们未来的生长和图案化。在果蝇发育过程中，条纹在这些边界的建立中起着重要的作用。已经确定了条纹的哺乳动物同源物，有证据表明，它们在脊椎动物的图案形成中扮演着类似的角色。具体地说，Lfng参与了躯体发生过程中发育边界的建立，并进一步被证明与新近描述的调节躯体发生的分段时钟有关。小鼠转基因将被用于从功能上识别顺式作用调控元件，这些元件控制Lfng的精确组织和发育受限表达，并将其表达模式与分段时钟联系在一起。这些区域的定位将有助于在DNA水平上识别这些调控元件。这些调控区域还将通过允许Lfng表达模式中其他家族成员的受控异位表达，在边缘基因家族的功能重叠研究中发挥关键作用。边缘蛋白在Notch信号通路的调控中起着关键作用，因此这些研究将直接关系到该通路在正常发育中的作用和调控。这一途径与多种人类疾病有关，包括癌症、Alagille综合征和CADASIL综合征，随着对潜在生物学知识的增加，对这些健康问题的进一步研究将得到加强。

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.