Developmental signaling through the wingless/frizzled pathway is an evolutionarily highly conserved mechanism that figures importantly in morphogenesis of many organs. Little information is available regarding the role of this pathway and its mediators in lung morphogenesis. We have examined the consequences of functional deletion of Wnt5a on lung development in mouse. The mutant mice have multiple developmental abnormalities and die shortly after birth with respiratory insufficiency. Preliminary data suggest that absence of Wnt5a results in increased cellular proliferation, enhanced pseudoglandular branching morphogenesis, increased overall lung/body size ration, but inhibits the maturation of the alveolar septa (thickened interstitium). Also, expression of Shh, Ptc, Fgfl0 and Bmp4 are all increased in Wnt5a(-/-) lungs. We propose that: Hypothesis: WNT5a affects fetal lung development through interactions with the SHH pathway.
Three Specific Aims are proposed to test the latter hypothesis.
Specific Aim 1. To further investigate the role Wnt5a by generating & characterizing SpC: Wnt5a transgenic mice.
Specific Aim 2. To determine the interactions of SHH & WNT signaling in lung development.
Specific Aim 3. To determine receptor specificity and intracellular mediators of WNT5a pathway in the lung. Characterization of the precise role of Wnt5a will contribute to our understanding of cell-to-cell communication and lung development. This information will be of utility in understanding the molecular mechanisms of congenital and induced lung disease.
