Expression of histone deacetylase 3 instructs alveolar type I cell differentiation by regulating a Wnt signaling niche in the lung

The commitment and differentiation of the alveolar type I (AT1) cell lineage is a critical step for the formation of distal lung saccules, which are the primitive alveolar units required for postnatal respiration. How AT1 cells arise from the distal lung epithelial progenitor cells prior to birth and whether this process depends on a developmental niche instructed by mesenchymal cells is poorly understood. We show that mice lacking histone deacetylase 3 specifically in the developing lung mesenchyme display lung hypoplasia including decreased mesenchymal proliferation and a severe impairment of AT1 cell differentiation. This is correlated with a decrease in Wnt/β-catenin signaling in the lung epithelium. We demonstrate that inhibition of Wnt signaling causes defective AT1 cell lineage differentiation ex vivo. Importantly, systemic activation of Wnt signaling at specific stages of lung development can partially rescue the AT1 cell differentiation defect in vivo. These studies show that histone deacetylase 3 expression generates an important developmental niche in the lung mesenchyme through regulation of Wnt signaling, which is required for proper AT1 cell differentiation and lung sacculation.