Submucosal gland development in the airway is controlled by Lymphoid Enhancer Binding Factor 1 (LEF1)

Previous studies have demonstrated that transcription of the lymphoid enhan cer binding factor 1 (Lef1) gene is upregulated in submucosal gland progeni tor cells just prior to gland bud formation in the developing ferret trache a, In the current report, several animal models were utilized to functional ly investigate the role of LEF1 in initiating and supporting gland developm ent in the airway. Studies on Lef1-deficient mice and antisense oligonucleo tides in a ferret xenograft model demonstrate that LEF1 is functionally req uired for submucosal gland formation in the nasal and tracheal mucosa, To d etermine whether LEF1 expression was sufficient for the induction of airway submucosal glands, two additional model systems were utilized, In the firs t, recombinant adeno-associated virus was used to overexpress the human LEF 1 gene in a human bronchial xenograft model of regenerative gland developme nt in the adult airway, In a second model, the LEF1 gene was ectopically ov erexpressed under the direction of the proximal airway-specific CC10 promot er in transgenic mice, In both of these models, morphometric analyses revea led no increase in the number or size of airway submucosal glands, indicati ng that ectopic LEF1 expression alone is insufficient to induce submucosal gland development. In summary, these studies demonstrate that LEF1 expressi on is required, but in and of itself is insufficient, for the initiation an d continued morphogenesis of submucosal glands in the airway.