LUNATIC FRINGE, SOMITOGENESIS AND SEGMENTATION CLOCKS

在发育过程中，细胞场内边界的建立可以指导它们未来的生长和模式。在果蝇发育过程中，边缘在这些边界的建立中起着重要的作用。边缘的哺乳动物同源物已被确定，证据表明它们在脊椎动物图案中起着类似的作用。具体来说，已经证明Lunatic fringe （lfg）参与了在躯体发生过程中建立发育边界，并进一步证明与新描述的调节躯体发生的分割时钟有关。小鼠转基因将用于功能性鉴定顺式作用调控元件，这些元件控制精确的组织和发育受限的lfg表达，并将其表达模式与分割时钟联系起来。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的功能重叠研究中发挥关键作用，允许在lfg表达模式中控制其他家族成员的异位表达。边缘蛋白在Notch信号通路的调节中起着关键作用，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，对这些健康问题的进一步研究将通过增加对潜在生物学的了解而得到加强。

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.