FGFs and their receptors in mouse embryonic lung development

Erwin Schrödinger Fellowship J 1959 LGFs and their receptors in mouse embryonic lung development Anne- Karina PERL 26.6.2000 The function of fibroblast growth factors (FGF) and their receptors (FGFR) in the development of the respiratory system appears to be conserved throughout many phyla. The drosophila melanogaster FGF homologue branchless functions in the branching morphogenesis of the tracheal system (Sutherland and Samakolis et al. 1996) as does its receptor , breathless (Glazer and Shilo 1991). The SP-C promoter has been used to direct expression of a membrane bound dnFGFR2b to the lung. Lack of FGFR2b function resulted in very rudimentary lungs. (Peters et al. 1994). Dominant negative transgenic approaches can be used to overcome early embryonic lethality and functional redundancies in FGF and FGFR families. I plan to use the inducible tetracycline system in combination with cell type specific expression pattern to express either a membrane bound dnFGFR1c, or a soluble dnFGFR2b (Celli 1998) in the developing lung only upon et induction. Therefore timed expression of these mutant receptors would be possible and studies on the effect of dominant-negative receptor expression during different stages of lung development, especially at late timepoints during development, will be practicable. Gene disruption experiments have been insufficient to resolve the role of FGFRl and FGFR2 during lung morphogenesis, since animals deficient in both of these die well before the onset of lung development (Deng et al., 1994) so the impact of these genes on organogenesis remains unclear. To access these questions we want to use the inducible Cre recombinase system to inactivate gene function time and tissue specific. Using these inducible systems to interfere with FGF function during lung morphogenesis and repair after injury will help to dissect downstream signaling cascades of FGF.