Genetische Kontrolle der Notochordentwicklung: Analyse der truncate Mutation der Maus

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During the previous funding period we identified the mouse homeobox gene Noto as pivotal for early embryo patterning. Noto is expressed in the node and nascent notochord, and as demonstrated by a null allele that we generated essential for node development, genesis of normal 9+0 cilia, and establishment of left-right asymmetry. We have identified Foxjl, a transcription factor expressed in the node and in ciliated cells of other tissues, as potential target of Noto. Foxjl is required for formation of 9+2 cilia, polarized organization of the cytoskeleton in the respiratory epithelium, and for establishment of left-right asymmetry, although Foxjl mutant nodes have cilia. Similarities of cellular phenotypes suggest that Noto acts at least in part through FoxjL TCF/LEF and Smad binding sites in the Noto promoter suggest that Wnt and TGFß signals regulate Noto expression. In this proposal we will test the hypotheses that i) Foxjl is required downstream of Noto to mediate major aspects of node and cilia development in mouse embryos, and ii) Wnt and TGFß signals regulate Noto expression. In addition we will further characterize the cellular defects in Noto mutants and delineate genomic regions that direct node and notochord-specific expression of Noto. Together, the results of this proposal will elucidate how Noto directs essential early patterning processes.