The Homeobox Transcription Factor Cux1 Coordinates Postnatal Epithelial Developmental Timing but Is Dispensable for Lung Organogenesis and Regeneration.

Lung epithelial progenitors use a complex network of known and predicted transcriptional regulators to influence early lung development. Here, we evaluate the function of one predicted regulator, Cux1, that we identified from transcriptional regulatory analysis of the SOX9+ distal lung progenitor network. We generated a new Cux1-floxed mouse model and created an epithelial-specific knockout of Cux1 using Shh-Cre (Cux1^ShhCre-LOF). Postnatal Cux1^ShhCre-LOF animals recapitulated key skin phenotypic features found in prior constitutive Cux1 knockout animals, confirming functionality of our new floxed model. Postnatal Cux1^ShhCre-LOF mice displayed subtle alveolar simplification and a transient delay in alveologenesis and alveolar type 1 cell development without persistent lung phenotypes. Cux1^ShhCre-LOF mice developed failure to thrive in their second and third weeks of life due to delayed ileal maturation, which similarly resolves by postnatal day 35. Finally, we challenged Cux1^ShhCre-LOF with influenza-mediated lung injury to demonstrate that Cux1^ShhCre-LOF mice undergo productive alveolar regeneration that is indistinguishable from WT animals. Together, these findings indicate that epithelial-specific loss of Cux1 leads to transient developmental delays in the skin, lung, and intestine without defects in definitive organogenesis. We conclude that Cux1 function is required for temporal optimization of developmental maturation in multiple organs with implications for susceptibility windows in developmental disease pathogenesis.