Title:
A β-catenin/Sox2/p63 Signaling Axis Regulates the Fate of Developing Airway Epithelium
Shuichi Hashimoto1,2,3, M.D.＆Ph.D.
1 Department of Pathology and Experimental Medicine, Kumamoto University Graduate School of Medical Sciences, 1-1-1 Honjo, Kumamoto 860-8556, Japan,
2 Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and3Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA
Abstract:
Canonical Wnt/β-catenin signaling has been shown to play critical roles in the regulation of fate decisions in the developing lung endoderm. However, downstream targets of canonical Wnt signaling that mediate these effects are poorly understood. We approached this question by expressing a stabilized form of β-catenin through Cre recombinase-mediated activation of aCtnnb1 (ex3)flox allele. To achieve this Cre recombinase was expressed under the control of either the SP-C or CCSP promoters ( Sftpc- or CCSP-Cre;Ctnnb1 (ex3)flox mice), allowing activation of canonical Wnt signaling in early or late embryonic lung endoderm, respectively. Sftpc-Cre(+)/Ctnnb1 (ex3)flox mice exhibited impaired normal bronchiolar development including cyst-like dilations of airways. The recombined bronchiolar epithelium showed proliferation arrest and did not express typical lung epithelial markers such as CCSP, acetylated tubulin (ACT) (ciliated cell marker), Pro SP-C, T1-α (Type I alveolar cell marker), Muc5ac or CGRP. We further demonstrated the altered signaling of several molecules important for cell fate specification. Specifically, Sox2 and p63 were repressed, and Sox9, Lef1 and TCF1 were induced. We show that conditional deletion of either Sox2 or p63 within lung epithelial cells recapitulate some of the defects in epithelial cell differentiation observed by activation of canonical Wnt signaling. In summary, canonical Wnt signaling negatively regulates Sox2 and p63 within airways leading to altered differentiation of bronchiolar epithelium. Thus, a β-catenin/Sox2/p63 signaling axis is important for lineage specification within developing lung endoderm.
