Sox2 is required for maintenance and differentiation of bronchiolar Clara, ciliated, and goblet cells.
Sox2 is required for maintenance and differentiation of bronchiolar Clara, ciliated, and goblet cells.
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DOI：
10.1371/journal.pone.0008248
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发表时间：
2009-12-14
期刊：
影响因子：
3.7
通讯作者：
Whitsett JA
中科院分区：
文献类型：
--
作者：
Tompkins DH;Besnard V;Lange AW;Wert SE;Keiser AR;Smith AN;Lang R;Whitsett JA
小鼠肺的细支气管由简单的柱状上皮构成，由纤毛细胞、Clara细胞和杯状细胞组成，这些细胞共同调节屏障功能、粘液纤毛清除和对肺内环境稳定至关重要的天然宿主防御。在目前的工作中，我们证明了Sox2在Clara细胞中的表达是纤毛细胞、Clara细胞和杯状细胞分化所必需的，这些细胞排列在出生后肺的细支气管处。利用Scgb1a1-Cre在Clara细胞中选择性地缺失该基因，导致在围产期和出生后发育过程中细支气管内Sox2的进行性丢失。细支气管细胞增殖率降低，形成未分化的立方鳞状上皮，缺乏Clara细胞(Scgb1a1)、纤毛细胞(FoxJ1和α微管蛋白)和杯状细胞(SPDEF和MUC5AC)的表达。成年后，细支气管壁上皮细胞数量减少，SOX2缺失，此时残留的SOX2表达主要局限于CGRP染色的神经上皮细胞的选择性壁龛。在缺乏SOX2的呼吸道上皮中，过敏原诱导的杯状细胞分化和粘液产生是不存在的。在体外，Sox2激活的启动子-荧光素酶报告基因分别构建了Clara、纤毛和杯状细胞Scgb1a1、FoxJ1和Ag2特有的分化标记。在体外，SOX2与Smad3发生物理相互作用，抑制转化生长因子-β1/Smad3介导的转录活性，这是一条负向调节增殖的途径。SOX2对Clara细胞的增殖和分化是必需的，Clara细胞是Clara、纤毛细胞和杯状细胞的来源。
The bronchioles of the murine lung are lined by a simple columnar epithelium composed of ciliated, Clara, and goblet cells that together mediate barrier function, mucociliary clearance and innate host defense, vital for pulmonary homeostasis. In the present work, we demonstrate that expression of Sox2 in Clara cells is required for the differentiation of ciliated, Clara, and goblet cells that line the bronchioles of the postnatal lung. The gene was selectively deleted in Clara cells utilizing Scgb1a1-Cre, causing the progressive loss of Sox2 in the bronchioles during perinatal and postnatal development. The rate of bronchiolar cell proliferation was decreased and associated with the formation of an undifferentiated, cuboidal-squamous epithelium lacking the expression of markers of Clara cells (Scgb1a1), ciliated cells (FoxJ1 and α-tubulin), and goblet cells (Spdef and Muc5AC). By adulthood, bronchiolar cell numbers were decreased and Sox2 was absent in extensive regions of the bronchiolar epithelium, at which time residual Sox2 expression was primarily restricted to selective niches of CGRP staining neuroepithelial cells. Allergen-induced goblet cell differentiation and mucus production was absent in the respiratory epithelium lacking Sox2. In vitro, Sox2 activated promoter-luciferase reporter constructs for differentiation markers characteristic of Clara, ciliated, and goblet cells, Scgb1a1, FoxJ1, and Agr2, respectively. Sox2 physically interacted with Smad3 and inhibited TGF-β1/Smad3-mediated transcriptional activity in vitro, a pathway that negatively regulates proliferation. Sox2 is required for proliferation and differentiation of Clara cells that serve as the progenitor cells from which Clara, ciliated, and goblet cells are derived.
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影响因子：
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作者：
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