Epithelial inactivation of Yy1 abrogates lung branching morphogenesis. Mus musculus

Yin Yang 1 (YY1) is a multifunctional zinc-finger-containing transcription factor that plays crucial roles in numerous biological processes by selectively activating or repressing transcription, depending upon promoter contextual differences and specific protein interactions. In mice, Yy1 null mutants die early in gestation while Yy1 hypomorphs die at birth from lung defects. We studied how the epithelial-specific inactivation of Yy1 impacts on lung development. The Yy1 mutation in lung epithelium resulted in neonatal death due to respiratory failure. It impaired tracheal cartilage formation, altered cell differentiation, abrogated lung branching, and caused airway dilation similar to those seen in human congenital cystic lung diseases. The cystic lung phenotype in Yy1 mutants can be explained by the reduced expression of Shh in lung endoderm, a transcriptional target of YY1, and the subsequent derepression of mesenchymal Fgf10 expression. Accordingly, SHH supplementation partially rescued the lung phenotype in vitro. Analysis of human lung tissues revealed decreased YY1 expression in children with pleuropulmonary blastoma (PPB), a rare pediatric lung tumor arising during fetal development and associated with DICER1 mutations. No evidence for a potential genetic interplay between murine Dicer and Yy1 genes during lung morphogenesis was observed. However, the cystic lung phenotype resulting from the epithelial inactivation of Dicer function mimics the Yy1 lung malformations with similar changes in Shh and Fgf10 expression. Together, our data demonstrate the critical requirement for YY1 in lung morphogenesis and identify Yy1 mutant mice as a potential model for studying the genetic basis of PPB. Overall design: Total RNA was isolated from lungs of E14.5 Shh+/Cre embryos (control), from E14.5 Shh+/Cre;Yy1flox/flox embryos (experimental), and from E14.5 Shh+/Cre;Dicerflox/flox embryos (experimental). Four specimens were analyzed per genotype.