Mist1 is necessary for the establishment of granule organization in serous exocrine cells of the gastrointestinal tract

Establishing a pool of granules at the luminal border is a key step during exocrine cell development in the pancreas and is necessary for efficient release of digestive enzymes through regulated exocytosis. Several proteins have been linked to maintaining granule organization, but it is unclear which regulatory mechanisms are necessary to establish organization. Based on temporal and spatial expression, the transcription factor Mist1 is an excellent candidate, and analysis of mice that do not express Mist1 (Mist1(KO)) reveal disrupted cell morphology in adult pancreatic acini. To address Mist1's role in establishing granule location, we have characterized the organization of pancreatic acini throughout development in Mist1(KO) mice. Using various histological approaches, we have determined that correct granule organization is never established in pancreatic acini of Mist1(KO) mice. Further examination indicates that this disruption in granule targeting may be the primary defect in MiSt1(KO) mice as granule organization is affected in other serous exocrine cells that normally express Mist1. To identify a mechanistic link between granule targeting and the loss of Mist1 function, intercellular junctions and the expression of RabD were assessed. While both of these factors are affected in Mist1(KO) mice, these changes alone do not account for the disorganization observed in MiStl(KO) tissues. Therefore, we conclude that Mist1 is necessary for complete differentiation and maturation of serous exocrine cells through the combined regulation of several exocrine specific genes. (C) 2004 Elsevier Ireland Ltd. All rights reserved.