LUNATIC FRINGE, SOMITOGENESIS AND SEGMENTATION CLOCKS

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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.