SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production
SPDEF is required for mouse pulmonary goblet cell differentiation and regulates a network of genes associated with mucus production
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DOI：
10.1172/jci39731
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发表时间：
2009-10-01
影响因子：
15.9
通讯作者：
Whitsett, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Chen, Gang;Korfhagen, Thomas R.;Whitsett, Jeffrey A.
各种急、慢性炎症刺激增加了产生粘液的杯状细胞的数量和活性，而杯状细胞的增殖和粘液的过度产生是慢性肺部疾病发病机制的核心。然而，人们对调控杯状细胞分化的转录程序知之甚少。在这里，我们证明了SAM指向的含有结构域的ETS样因子(SPDEF)控制着对小鼠肺杯状细胞分化至关重要的转录程序。最初的细胞谱系追踪分析表明，无纤毛的分泌上皮细胞，即Clara细胞，是体内肺变应原暴露诱导的杯状细胞的祖细胞。此外，在Clara细胞中体内表达SPDEF可在没有细胞增殖的情况下引起快速和可逆的杯状细胞分化。这与调控杯状细胞分化和蛋白糖基化的基因表达增强有关，包括叉头盒A3(FOXA3)、前梯度2(AG2)和氨基葡萄糖。(N-乙酰)转移酶3，粘蛋白类型(Gcnt3)。与这些发现一致的是，肺变应原致敏后小鼠的杯状细胞中SPDEF和FOXA3的水平增加，并且这两种蛋白共存于慢性肺病患者呼吸道内的杯状细胞中。小鼠SPDEF基因的缺失导致体内肺变应原暴露后，气管/喉粘膜下腺和传导气道上皮中没有杯状细胞。这些数据表明，SPDEF在调节转录网络中发挥着关键作用，该网络介导了与慢性肺疾病相关的杯状细胞分化和粘液过度产生。
Various acute and chronic inflammatory stimuli increase the number and activity of pulmonary mucus-producing goblet cells, and goblet cell hyperplasia and excess mucus production are central to the pathogenesis of chronic pulmonary diseases. However, little is known about the transcriptional programs that regulate goblet cell differentiation. Here, we show that SAM-pointed domain-containing Ets-like factor (SPDEF) controls a transcriptional program critical for pulmonary goblet cell differentiation in mice. Initial cell-lineage-tracing analysis identified nonciliated secretory epithelial cells, known as Clara cells, as the progenitors of goblet cells induced by pulmonary allergen exposure in vivo. Furthermore, in vivo expression of SPDEF in Clara cells caused rapid and reversible goblet cell differentiation in the absence of cell proliferation. This was associated with enhanced expression of genes regulating goblet cell differentiation and protein glycosylation, including forkhead box A3 (Foxa3), anterior gradient 2 (Agr2), and glucosaminyl. (N-acetyl) transferase 3, mucin type (Gcnt3). Consistent with these findings, levels of SPDEF and FOXA3 were increased in mouse goblet cells after sensitization with pulmonary allergen, and the proteins were colocalized in goblet cells lining the airways of patients with chronic lung diseases. Deletion of the mouse Spdef gene resulted in the absence of goblet cells in tracheal/laryngeal submucosal glands and in the conducting airway epithelium after pulmonary allergen exposure in vivo. These data show that SPDEF plays a critical role in regulating a transcriptional network mediating the goblet cell differentiation and mucus hyperproduction associated with chronic pulmonary disorders.