The Ets domain transcription factor Spdef drives maturation of Goblet and Paneth cells in the intestinal epithelium

BACKGROUND & AIMS: Stems cells within the intestinal epithelium generate daughter cells which undergo lineage commitment and maturation through the concerted action of the Wnt and Notch signalling cascades. Both pathways, in turn, regulate transcription factor networks which further define differentiation towards either enterocytes or one of three secretory cell lineages (Paneth, goblet or enteroendocrine cells). In this manuscript, we identified the Ets domain transcription factor, Spdef, as a novel lineage maker of goblet and Paneth cells. METHODS: To address the function of Spdef in vivo, we inactivated the Spdef gene and analysed the intestinal phenotype using a range of histological techniques and DNA microarray profiling. RESULTS: In accordance with the expression data we found that loss of Spdef severely impaired the maturation of goblet and Paneth cells and conversely lead to an accumulation of immature secretory progenitors. Moreover, we provide evidence suggesting that Spdef positively and negatively regulates a specific subset of goblet and Paneth cell genes including Cryptdins, Mmp7, Ang4, Kallikreins, and Muc2. CONCLUSION: We propose a model whereby Spdef acts downstream of Math1 to promote terminal differentiation of a secretory progenitor pool towards Paneth and goblet cells. Keywords: expression profiling To compare wild-type versus Spdef-/- intestinal or colonic tissue samples, pooled total RNA from 2-3 littermates were utilized for each experiment. In addition, tissue samples from both adult (P30) or E18.5 fetal mice were compared. Overall, we carried out 3 dye swap experiments for E18.5 small intestine and P30 colon resulting in 6 arrays each, and 2 dye swap experiments for E18.5 colon and P30 small intestine resulting in 4 arrays each.