β-Catenin Is Not Necessary for Maintenance or Repair of the Bronchiolar Epithelium

Abstract

Signaling by Wnt/beta-catenin regulates self-renewal of tissue stem cells in the gut and, when activated in the embryonic bronchiolar epithelium, leads to stem cell expansion. We have used transgenic and cell type-specific knockout strategies to determine roles for beta-catenin-regulated gene expression in normal maintenance and repair of the bronchiolar epithelium. Analysis of TOPGal transgene activity detected beta-catenin signaling in the steady-state and repairing bronchiolar epithelium. However, the broad distribution and phenotype of signaling cells precluded establishment of a clear role for beta-catenin in the normal or repairing state. Necessity of beta-catenin signaling was tested through Cre-mediated deletion of Catnb exons 2-6 in airway epithelial cells. Functional knockout of beta-catenin had no impact on expression of Clara cell differentiation markers, mitotic index, or sensitivity of these cells to the Clara cell-specific toxicant, naphthalene. Repair of the naphthalene-injured airway proceeded with establishment of focal regions of beta-catenin-null epithelium. The size of regenerative epithelial units, mitotic index, and restoration of the ciliated cell population did not vary between wild-type and genetically modified mice. Thus, beta-catenin was not necessary for maintenance or efficient repair of the bronchiolar epithelium.

Elf3 plays a role in regulating bronchiolar epithelial repair kinetics following Clara cell-specific injury

“…Regulation of gene expression is a very important aspect of many physiological and pathological processes, and there have only been few studies examining the role of various transcription factors in the pulmonary regenerative response to naphthalene-induced Clara cell damage. 4,6,9,33,40,41 In the present study, our findings suggest that Elf3 may play an important role in regulating airway epithelial repair kinetics, as the rate of bronchiolar epithelial cell proliferation and mitosis as well as Clara cell renewal was delayed in Elf3À/À mice after treatment with naphthalene. The absence of Elf3 appeared to have no observable effect on the extent of Clara cell injury in Elf3À/À mice, as there was no significant difference in the mean necrosis score between Elf3 þ / þ and Elf3À/À mice at any time point after naphthalene exposure.…”

Research on WISP1 in Lung Disease

“…Actually, the functional β-catenin/TCF heterodimeric transcription factor has been visualized in vivo, where β-galactosidase has been placed downstream from promoter elements harboring canonical TCF cis elements (e.g., TCFoptimized promoter-LacZ or TOPGAL mice) [55]. These TOPGAL mice have provided a sensitive approach for dissecting the role of the canonical β-catenin pathway in lung development [56], injury [57], and repair [58,54], as well as airway epithelial lineage and stem cell studies [59].…”

The building blocks of mammalian lung development

“…Wnt signaling is required for embryonic progenitor proliferation Goss et al, 2009). However, specific deletion of b-catenin, which is necessary for canonical Wnt signaling, in a known adult lung progenitor population did not have any effect on airway epithelial growth, maintenance or repair (Zemke et al, 2009). This suggests that Wnt signaling is dispensable for regulating postnatal bronchiolar stem or progenitor cells.…”