Duan D, Yue Y, Zhou W, Labed B, Ritchie T C, Grosschedl R, Engelhardt J F
Department of Anatomy and Cell Biology and Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa, USA.
Development. 1999 Oct;126(20):4441-53. doi: 10.1242/dev.126.20.4441.
Previous studies have demonstrated that transcription of the lymphoid enhancer binding factor 1 (Lef1) gene is upregulated in submucosal gland progenitor cells just prior to gland bud formation in the developing ferret trachea. In the current report, several animal models were utilized to functionally investigate the role of LEF1 in initiating and supporting gland development in the airway. Studies on Lef1-deficient mice and antisense oligonucleotides in a ferret xenograft model demonstrate that LEF1 is functionally required for submucosal gland formation in the nasal and tracheal mucosa. To determine whether LEF1 expression was sufficient for the induction of airway submucosal glands, two additional model systems were utilized. In the first, recombinant adeno-associated virus was used to overexpress the human LEF1 gene in a human bronchial xenograft model of regenerative gland development in the adult airway. In a second model, the LEF1 gene was ectopically overexpressed under the direction of the proximal airway-specific CC10 promoter in transgenic mice. In both of these models, morphometric analyses revealed no increase in the number or size of airway submucosal glands, indicating that ectopic LEF1 expression alone is insufficient to induce submucosal gland development. In summary, these studies demonstrate that LEF1 expression is required, but in and of itself is insufficient, for the initiation and continued morphogenesis of submucosal glands in the airway.
先前的研究表明，在发育中的雪貂气管中，黏膜下腺祖细胞中淋巴样增强子结合因子1（Lef1）基因的转录在腺芽形成之前就会上调。在本报告中，利用了几种动物模型来功能研究LEF1在启动和支持气道腺体发育中的作用。对Lef1基因敲除小鼠和雪貂异种移植模型中的反义寡核苷酸的研究表明，LEF1在鼻腔和气管黏膜的黏膜下腺形成中具有功能需求。为了确定LEF1表达是否足以诱导气道黏膜下腺，还使用了另外两种模型系统。第一种是在成人气道再生腺发育的人支气管异种移植模型中，使用重组腺相关病毒过表达人LEF1基因。在第二种模型中，LEF1基因在转基因小鼠中近端气道特异性CC10启动子的指导下异位过表达。在这两种模型中，形态计量学分析均显示气道黏膜下腺的数量或大小没有增加，这表明单独的异位LEF1表达不足以诱导黏膜下腺发育。总之，这些研究表明，LEF1表达对于气道黏膜下腺的起始和持续形态发生是必需的，但仅其本身是不够的。
