Regulation of lung progenitor cells differentiation by the Lin28A/Let-7 pathway

Lin28 is a RNA binding protein that regulates gene expression via inhibition of the Let-7 microRNA maturation. In vertebrates, Lin28A is highly expressed in stem and progenitor cells and play important roles in the balance between self-renewal, proliferation, and differentiation. We have shown previously that global Lin28A overexpression during mouse embryogenesis results in perinatal lethality. However, the reason for this early lethality has not been elucidated. Here we show that Lin28A overexpression and the resulting Let-7 downregulation prevent normal lung development, thus causing the perinatal lethality. Notably, we found that the Lin28A/Let-7 pathway delays the transition between one developmental stage of the lung epithelial progenitor cells to another but does not completely abrogate their differentiation capacity. Using the Cre-Lox system, we show that Lin28A expression in the embryonic lung mesenchymal cells is sufficient to recapitulate the epithelial lung phenotype derived by global Lin28A overexpression while its expression in the epithelial progenitor cells results in a much milder developmental phenotype. Finally, we defined the specific time window wherein Lin28A expression exerts its effect on the development of the lung and showed the relevance of our findings also for human lung development.

To conclude, our findings define the Lin28/Let-7 pathway as a heterochronic regulator of the lung progenitor cells’ differentiation and thus of the lung development as a whole. While the precise molecular mechanism of this heterochronic regulation is yet to be determined, we identified several pathways that might play a critical role in this process.