AN ACHAETE-SCUTE HOMOLOG ESSENTIAL FOR NEUROENDOCRINE DIFFERENTIATIONIN THE LUNG

In Drosophila and in vertebrates, the achaete-scute family of basic he lix-loop-helix transcription factors plays a critical developmental ro le in neuronal commitment and differentiation(1-6). Relatively little is known, however about the transcriptional control of neural features in cells outside a neuronal context. A minority of normal bronchial e pithelial cells and many Lung cancers, especially small-cell lung canc er, exhibit a neuroendocrine phenotype that may reflect a common precu rsor cell population(7-11). We show here that human achaete-scute homo logue-1 (hASW1) is selectively expressed in normal fetal pulmonary neu roendocrine cells, as well as in the diverse range of lung cancers wit h neuroendocfine features. Strikingly, newborn mice bearing a disrupti on of the ASR1 gene have no detectable pulmonary neuroendocrine cells. Depletion of this transcription factor from lung cancer cells by anti sense oligonucleotides results in a significant decrease in the expres sion of neuroendrocrine markers. Thus, a homologue of Drosophila neura l fate determination genes seems to be necessary for progression of lu ng epithelial cells through a neuroendocrine differentiation pathway t hat is a feature of small-cell lung cancer, the most. lethal form of h uman lung cancer.