Abstract
ABSTRACTMyosin ID (MYO1D) is a member of the class I myosin family. We screened 48,649 third generation (G3) germline mutant mice derived from N-ethyl-N-nitrosourea-mutagenized grandsires for intestinal homeostasis abnormalities after oral administration of dextran sodium sulfate (DSS). We found and validated mutations in Myo1d as a cause of increased susceptibility to DSS-induced colitis. MYO1D is produced in the intestinal epithelium, and the colitis phenotype is dependent on the nonhematopoietic compartment of the mouse. Moreover, MYO1D appears to couple cytoskeletal elements to lipid in an ATP-dependent manner. These findings demonstrate that MYO1D is needed to maintain epithelial integrity and protect against DSS-induced colitis.
Highlights
Inflammatory bowel diseases (IBDs) are characterized by a state of chronic gut inflammation, believed to have both genetic and environmental etiologies
We report that MYO1D is necessary for the maintenance of intestinal homeostasis and provide an initial phenotypic characterization of the colitis phenotype caused by loss of MYO1D function
The whisper phenotype was mapped to mutations in three genes on chromosome 11: kinase suppressor of Ras-1 (Ksr1) (P=7.2×10−9), Myo1d (P=7.2×10−9) and Ly6/PLAUR domain-containing 8 (Lypd8) (P=1.4×10−8) (Fig. 1A,B)
Summary
Inflammatory bowel diseases (IBDs) are characterized by a state of chronic gut inflammation, believed to have both genetic and environmental etiologies. Some monogenic forms of IBD have been described (Uhlig, 2013), the genetic component remains unknown in the great majority of cases. Most individuals rapidly repair the breach, eliminate or contain microbes that have entered the lamina propria and limit the inflammatory response, but some are unable to do so. Such individuals can be said to have defective intestinal homeostatic mechanisms
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