The roles of Inturned in mammalian lung development

Project Summary Congenital Lung Malformation (CLM) is a series of rare birth defects that in the most severe case are fatal at birth. The effective prevention and early intervention of these defects require a comprehensive understanding of the mechanisms underlying the morphogenesis of the embryonic lungs. The PI found that mouse embryos mutant for the CPLANE (cilia and planar polarity effector) protein Intu exhibited severe defects in the growth and airway branching of the embryonic lungs. The PI will test the hypothesis that loss of Intu leads to severe loss of cilia formation, hence compromised cilia- dependent Hh and PDGF signaling. He will examine whether loss of Intu affects Hh and PDGF pathway outputs in vivo and the response of the lung tissue to Shh and PDGF in culture. He will also test the genetic interaction between Intu and a key regulator of Hh pathway, Gli2, in lung morphogenesis. Subsequently, He will examine the impact of Intu mutation on signaling pathways and tissue patterning in embryonic lung development through a candidate gene approach, in which known regulators of lung development will be examined. He will subsequently examine whether Intu mutation alters the proliferation and programmed cell death in lung development. Finally, the PI will take a transcriptomics approach, to compare the transcriptional profiles between wild type and Intu mutant lungs. The proposed research will reveal the roles of CPLANE proteins and cilia in embryonic lung development, and contribute to the better understanding of lung diseases such as CLM.