title: Requirement of matrix metalloproteinase-1 for intestinal homeostasis in the adult Drosophila midgut.
abstract: Stem cells are tightly regulated by both intrinsic and extrinsic signals as well as the extracellular matrix (ECM) for tissue homeostasis and regenerative capacity. Matrix metalloproteinases (MMPs), proteolytic enzymes, modulate the turnover of numerous substrates, including cytokine precursors, growth factors, and ECM molecules. However, the roles of MMPs in the regulation of adult stem cells are poorly understood. In the present study, we utilize the Drosophila midgut, which is an excellent model system for studying stem cell biology, to show that Mmp1 is involved in the regulation of intestinal stem cells (ISCs). The results showed that Mmp1 is expressed in the adult midgut and that its expression increases with age and with exposure to oxidative stress. Mmp1 knockdown or Timp-overexpressing flies and flies heterozygous for a viable, hypomorphic Mmp1 allele increased ISC proliferation in the gut, as shown by staining with an anti-phospho-histone H3 antibody and BrdU incorporation assays. Reduced Mmp1 levels induced intestinal hyperplasia, and the Mmp1depletion-induced ISC proliferation was rescued by the suppression of the EGFR signaling pathway, suggesting that Mmp1 regulates ISC proliferation through the EGFR signaling pathway. Furthermore, adult gut-specific knockdown and whole-animal heterozygotes of Mmp1 increased additively sensitivity to paraquat-induced oxidative stress and shortened lifespan. Our data suggest that Drosophila Mmp1 is involved in the regulation of ISC proliferation for maintenance of gut homeostasis.
authors.affiliation: Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Shin-Hae
authors.initials: SH
authors.lastname: Lee
authors.forename: Joung-Sun
authors.initials: JS
authors.lastname: Park
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Kim
authors.forename: Hae-Young
authors.initials: HY
authors.lastname: Chung
authors.forename: Mi-Ae
authors.initials: MA
authors.lastname: Yoo
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004331:Drosophila melanogaster / Q000201:enzymology*; D020895:Enterocytes / Q000201:enzymology; D066246:ErbB Receptors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006706:Homeostasis; D006965:Hyperplasia / Q000201:enzymology; D007422:Intestines / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D008017:Life Expectancy; D020781:Matrix Metalloproteinase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008940:Mitotic Index; D018384:Oxidative Stress; D034622:RNA Interference; D055153:Stem Cell Niche; D013234:Stem Cells / Q000201:enzymology / Q000473:pathology
chemical_list: D066246:ErbB Receptors; D020781:Matrix Metalloproteinase 1