Abstract
We identified NPAS3 as a mouse homolog of Drosophila Trachealess (TRL), which regulates fly tracheogenesis, and now test the hypothesis that NPAS3 controls lung formation by altering expression of downstream genes critical for normal development. Gene expression was determined by QRT‐PCR and immunohistochemistry. NPAS3‐null (KO) mice were generated. Pulmonary function was assessed in adult mice with the Flexivent apparatus. Npas3 gene expression peaks in lung from E10.5‐E13.5, verified by sequencing, with immunostaining in airway epithelial cells. NPAS3‐KO mice have reduced lung branching morphogenesis and are viable in utero, but newborns die in respiratory distress, with decreased alveolarization. At P1, KO lungs have decreased Shh, FGF9, FGF10, and BMP4 mRNAs, and increased Sprouty2 mRNA, consistent with reduced FGF signaling. Branching morphogenesis of E11.5 KO lung buds is rescued by FGF10, but not cell migration. NPAS3‐deficient heterozygotes survive postnatally but develop emphysema and airways hyper‐reactivity. Thus, NPAS3 controls expression of multiple signaling cascades important for lung development. NPAS3 deficiency may also predispose to chronic lung disease.
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