Foxl1 is a winged helix transcription factor expressed in the mesenchyme of the gastrointestinal tract. In the absence of Foxl1, parietal cells fail to secrete gastric acid in response to various secretagogue stimuli including cAMP. A marked decrease in H+, K+, ATPase expression was observed even though a substantial number of parietal cells still existed in Foxl1-deficient mice. Ultrastructural analysis suggested that the gastric acid secretion defect in Foxl1-deficient mice is mainly due to impairment in the fusion of cytoplasmic tubulovesicular structures to the apical canalicular plasma membrane. Among the molecules involved in the membrane fusion event, only SNAP25 showed a significant decrease in mRNA expression, which likely caused the impairment in acid secretion from parietal cells in Foxl1-deficient mice, with the reduction in H+,K+ -ATPase expression contributing to additional effect. (C) 2004 Elsevier Inc. All rights reserved.