Po-Nien Tsao, Michelle Vasconcelos, Konstantin I. Izvolsky, Jun Qian, Jining Lu, and Wellington V. Cardoso
Although there is accumulated evidence of a role for Notch in the
developing lung, it is still unclear how disruption of Notch signaling affects
lung progenitor cell fate and differentiation events in the airway epithelium.
To address this issue, we inactivated Notch signaling conditionally in the
endoderm using a Shh-Cre deleter mouse line and mice carrying floxed
alleles of the Pofut1 gene, which encodes an O-fucosyltransferase
essential for Notch-ligand binding. We also took the same conditional approach
to inactivate expression of Rbpjk, which encodes the transcriptional
effector of canonical Notch signaling. Strikingly, these mutants showed an
almost identical lung phenotype characterized by an absence of secretory Clara
cells without evidence of cell death, and showed airways populated essentially
by ciliated cells, with an increase in neuroendocrine cells. This phenotype
could be further replicated in cultured wild-type lungs by disrupting Notch
signaling with a gamma-secretase inhibitor. Our data suggest that Notch acts
when commitment to a ciliated or non-ciliated cell fate occurs in proximal
progenitors, silencing... |