| Summary: | WNT5a is a mainly “non-canonical” WNT ligand whose dysregulation is observed in lung diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma. Germline deletion of <i>Wnt5a</i> disrupts embryonic lung development. However, the temporal-specific function of WNT5a remains unknown. In this study, we generated a conditional loss-of-function mouse model (<i>Wnt5a<sup>CAG</sup></i>) and examined the specific role of <i>Wnt5a</i> during the saccular and alveolar phases of lung development. The lack of <i>Wnt5a</i> in the saccular phase blocked distal airway expansion and attenuated differentiation of endothelial and alveolar epithelial type I (AT1) cells and myofibroblasts. Postnatal <i>Wnt5a</i> inactivation disrupted alveologenesis, producing a phenotype resembling human bronchopulmonary dysplasia (BPD). Mutant lungs showed hypoalveolization, but endothelial and epithelial differentiation was unaffected. The major impact of <i>Wnt5a</i> inactivation on alveologenesis was on myofibroblast differentiation and migration, with reduced expression of key regulatory genes. These findings were validated in vitro using isolated lung fibroblasts. Conditional inactivation of the WNT5a receptors <i>Ror1</i> and <i>Ror2</i> in alveolar myofibroblasts recapitulated the <i>Wnt5a<sup>CAG</sup></i> phenotype, demonstrating that myofibroblast defects are the major cause of arrested alveologenesis in <i>Wnt5a<sup>CAG</sup></i> lungs. Finally, we show that <i>WNT5a</i> is reduced in human BPD lung samples, indicating the clinical relevance and potential role for WNT5a in pathogenesis of BPD.
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