SIM2 maintains innate host defense of the small intestine

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 307; no. 11; pp. G1044 - G1056
• Main Authors: Chen, Kuan-Jung, Lizaso, Analyn, Lee, Ying-Hue
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2014
• Subjects: Alkaline Phosphatase - metabolism; Animals; Antimicrobial Cationic Peptides - metabolism; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - physiology; Cell Count; Chromosomes; Down syndrome; Female; Gastric Emptying - genetics; Gastric Emptying - physiology; Gastrointestinal Tract - metabolism; Gastrointestinal Tract - pathology; Immunity, Innate - genetics; In Vitro Techniques; Insects; Intestinal Absorption - genetics; Intestinal Absorption - physiology; Intestine, Small - immunology; Intestine, Small - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nervous system; Peptides; Peristalsis - genetics; Peristalsis - physiology; Proteins; Small intestine; single-minded 2 protein; antimicrobial peptide; intestinal innate immunity; cryptdin; T cell factor 7-like 2
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00241.2014

The single-minded 2 (SIM2) protein is a basic helix-loop-helix transcription factor regulating central nervous system (CNS) development in Drosophila. In humans, SIM2 is located within the Down syndrome critical region on chromosome 21 and may be involved in the development of mental retardation phenotype in Down syndrome. In this study, knockout of SIM2 expression in mice resulted in a gas distention phenotype in the gastrointestinal tract. We found that SIM2 is required for the expression of all cryptdins and numerous other antimicrobial peptides (AMPs) expressed in the small intestine. The mechanism underlying how SIM2 controls AMP expression involves both direct and indirect regulations. For the cryptdin genes, SIM2 regulates their expression by modulating transcription factor 7-like 2, a crucial regulator in the Wnt/β-catenin signaling pathway, while for other AMP genes, such as RegIIIγ, SIM2 directly activates their promoter activity. Our results establish that SIM2 is a crucial regulator in controlling expression of intestinal AMPs to maintain intestinal innate immunity against microbes.