title: MicroRNA-29b regulates the expression level of human progranulin, a secreted glycoprotein implicated in frontotemporal dementia.
abstract: Progranulin deficiency is thought to cause some forms of frontotemporal dementia (FTD), a major early-onset age-dependent neurodegenerative disease. How progranulin (PGRN) expression is regulated is largely unknown. We identified an evolutionarily conserved binding site for microRNA-29b (miR-29b) in the 3' untranslated region (3'UTR) of the human PGRN (hPGRN) mRNA. miR-29b downregulates the expression of luciferase through hPGRN or mouse PGRN (mPGRN) 3'UTRs, and the regulation was abolished by mutations in the miR-29b binding site. To examine the direct effect of manipulating endogenous miR-29b on hPGRN expression, we established a stable NIH3T3 cell line that expresses hPGRN under the control of the cytomegalovirus promoter. Ectopic expression of miR-29b decreased hPGRN expression at the both mRNA and protein levels. Conversely, knockdown of endogenous miR-29b with locked nucleic acid increased the production and secretion of hPGRN in NIH3T3 cells. Endogenous hPGRN in HEK 293 cells was also regulated by miR-29b. These findings identify miR-29b as a novel posttranscriptional regulator of PGRN expression, raising the possibility that miR-29b or other miRNAs might be targeted therapeutically to increase hPGRN levels in some FTD patients.
authors.affiliation: Gladstone Institute of Neurological Disease, Department of Neurology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Jiao
authors.forename: Lauren D
authors.initials: LD
authors.lastname: Herl
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: Fen-Biao
authors.initials: FB
authors.lastname: Gao
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D057180:Frontotemporal Dementia / Q000235:genetics*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D042541:Intracellular Space / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D000077153:Progranulins; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C492314:GRN protein, human; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D000077153:Progranulins; D012333:RNA, Messenger; D008156:Luciferases