Stabilized beta-catenin in lung epithelial cells changes cell fate and leads to tracheal and bronchial polyposis.
The precise mechanisms by which beta-catenin controls morphogenesis and cell differentiation remain largely unknown. Using embryonic lung development as a model, we deleted exon 3 of beta-catenin via Nkx2.1-cre in the Catnb[+/lox(ex3)] mice and studied its impact on epithelial morphogenesis. Robust selective accumulation of truncated, stabilized beta-catenin was found in Nkx2.1-cre;Catnb[+/lox(ex3)] lungs that were associated with the formation of polyp-like structures in the trachea and main-stem bronchi. Characterization of polyps suggests that accumulated beta-catenin impacts epithelial morphogenesis in at least two ways. "Intracellular" accumulation of beta-catenin blocked differentiation of spatially-appropriate airway epithelial cell types, Clara cells, ciliated cells and basal cells, and activated UCHL1, a marker for pulmonary neuroendocrine cells. There was also evidence for a "paracrine" impact of beta-catenin accumulation, potentially mediated via activation of Bmp4 that inhibited Clara and ciliated, but not basal cell differentiation. Thus, excess beta-catenin can alter cell fate determination by both direct and paracrine mechanisms.
Li
Changgong
C
Department of Pediatrics, Women's and Children's Hospital, USC Keck School of Medicine, Los Angeles, CA 90033, USA. changgon@usc.edu
Li
Aimin
A
Li
Min
M
Xing
Yiming
Y
Chen
Hongyan
H
Hu
Lingyan
L
Tiozzo
Caterina
C
Anderson
Stewart
S
Taketo
Makoto Mark
MM
Minoo
Parviz
P
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D055745:Bronchioles / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005838:Genotype; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D055099:Neuroendocrine Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000074482:Thyroid Nuclear Factor 1; D014132:Trachea / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D055415:Bone Morphogenetic Protein 4; C495267:CTNNB1 protein, mouse; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051176:beta Catenin; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse