The Ets-Domain Transcription Factor Spdef Promotes Maturation of Goblet and Paneth Cells in the Intestinal Epithelium

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 137; no. 4; pp. 1333 - 1345.e3
• Main Authors: Gregorieff, Alex, Stange, Daniel E, Kujala, Pekka, Begthel, Harry, van den Born, Maaike, Korving, Jeroen, Peters, Peter J, Clevers, Hans
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2009
• Subjects: Animals; Biomarkers - metabolism; Cell Differentiation - genetics; Cell Lineage; Colon - metabolism; Colon - ultrastructure; Gastroenterology and Hepatology; Gene Expression Profiling - methods; Gene Expression Regulation; Genotype; Goblet Cells - metabolism; Goblet Cells - ultrastructure; Intestine, Small - metabolism; Intestine, Small - ultrastructure; Mice; Mice, Inbred C57BL; Mice, Knockout; Oligonucleotide Array Sequence Analysis; Paneth Cells - metabolism; Paneth Cells - ultrastructure; Phenotype; Proto-Oncogene Proteins c-ets - deficiency; Proto-Oncogene Proteins c-ets - genetics; Proto-Oncogene Proteins c-ets - metabolism; Stem Cells - metabolism; Stem Cells - ultrastructure; Transcription, Genetic; PAS; significant analysis of microarrays; E; Mammalian Gene Collection; MGC; Gene Expression Omnibus; GEO; embryonic; kilobase; periodic acid-Schiff; RT-PCR; kb; reverse-transcription polymerase chain reaction; SAM
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2009.06.044

Background & Aims Stem cells within the intestinal epithelium generate daughter cells that undergo lineage commitment and maturation through the combined action of the Wnt and Notch signaling cascades. Both pathways, in turn, regulate transcription factor networks that further define differentiation toward either enterocytes or 1 of 3 secretory cell lineages (Paneth, goblet, or enteroendocrine cells). In this study, we investigated the role of the Wnt-responsive, Ets-domain transcription factor Spdef in the differentiation of goblet and Paneth cells. Methods The in vivo function of Spdef was examined by disrupting the Spdef gene in mice ( Spdef −/− mice) and analyzing the intestinal phenotype using a range of histologic techniques and DNA microarray profiling. Results In accordance with expression data, we found that loss of Spdef severely impaired the maturation of goblet and Paneth cells and, conversely, led to an accumulation of immature secretory progenitors. Spdef appears to positively and negatively regulate a specific subset of goblet and Paneth cell genes, including Cryptdins , Mmp7 , Ang4 , Kallikreins , and Muc2. Conclusions Spdef acts downstream of Math1 to promote terminal differentiation of a secretory progenitor pool into Paneth and goblet cells.