Noncanonical role of transferrin receptor 1 is essential for intestinal homeostasis.
Transferrin receptor 1 (Tfr1) facilitates cellular iron uptake through receptor-mediated endocytosis of iron-loaded transferrin. It is expressed in the intestinal epithelium but not involved in dietary iron absorption. To investigate its role, we inactivated the Tfr1 gene selectively in murine intestinal epithelial cells. The mutant mice had severe disruption of the epithelial barrier and early death. There was impaired proliferation of intestinal epithelial cell progenitors, aberrant lipid handling, increased mRNA expression of stem cell markers, and striking induction of many genes associated with epithelial-to-mesenchymal transition. Administration of parenteral iron did not improve the phenotype. Surprisingly, however, enforced expression of a mutant allele of Tfr1 that is unable to serve as a receptor for iron-loaded transferrin appeared to fully rescue most animals. Our results implicate Tfr1 in homeostatic maintenance of the intestinal epithelium, acting through a role that is independent of its iron-uptake function.
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27705;
Alan C
AC
Chen
Division of Pharmacology and Preclinical Biology, Scholar Rock, Cambridge, MA 02142;
Adriana
A
Donovan
Division of Laboratory Systems, Center for Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention, Atlanta, GA 30333;
Renee
R
Ned-Sykes
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC 27705; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27705 nancy.andrews@duke.edu.
Nancy C
NC
Andrews
D000483:Alleles; D000818:Animals; D001921:Brain / Q000196:embryology; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000196:embryology*; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D011990:Receptors, Transferrin / Q000502:physiology*; D011995:Recombination, Genetic; D013234:Stem Cells / Q000166:cytology
D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D007501:Iron
epithelial–mesenchymal transition; homeostasis; intestinal epithelium; stem cell; transferrin receptor