Li Changgong, Li Aimin, Li Min, Xing Yiming, Chen Hongyan, Hu Lingyan, Tiozzo Caterina, Anderson Stewart, Taketo Makoto Mark, Minoo Parviz
Department of Pediatrics, Women's and Children's Hospital, USC Keck School of Medicine, Los Angeles, CA 90033, USA.
Dev Biol. 2009 Oct 1;334(1):97-108. doi: 10.1016/j.ydbio.2009.07.021. Epub 2009 Jul 23.
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.
β-连环蛋白控制形态发生和细胞分化的确切机制在很大程度上仍然未知。我们以胚胎肺发育为模型，通过Nkx2.1-cre在Catnb[+/lox(ex3)]小鼠中删除β-连环蛋白的外显子3，并研究其对上皮形态发生的影响。在Nkx2.1-cre;Catnb[+/lox(ex3)]肺中发现了截短的、稳定的β-连环蛋白的强烈选择性积累，这与气管和主支气管中息肉样结构的形成有关。息肉的特征表明，积累的β-连环蛋白至少通过两种方式影响上皮形态发生。β-连环蛋白的“细胞内”积累阻止了空间上合适的气道上皮细胞类型（克拉拉细胞、纤毛细胞和基底细胞）的分化，并激活了UCHL1，这是一种肺神经内分泌细胞的标志物。也有证据表明β-连环蛋白积累具有“旁分泌”作用，可能是通过激活Bmp4介导的，Bmp4抑制了克拉拉细胞和纤毛细胞的分化，但不抑制基底细胞的分化。因此，过量的β-连环蛋白可以通过直接和旁分泌机制改变细胞命运的决定。
