title: miR-21 represses Pdcd4 during cardiac valvulogenesis.
abstract: The discovery of small non-coding microRNAs has revealed novel mechanisms of post-translational regulation of gene expression, the implications of which are still incompletely understood. We focused on microRNA 21 (miR-21), which is expressed in cardiac valve endothelium during development, in order to better understand its mechanistic role in cardiac valve development. Using a combination of in vivo gene knockdown in zebrafish and in vitro assays in human cells, we show that miR-21 is necessary for proper development of the atrioventricular valve (AV). We identify pdcd4b as a relevant in vivo target of miR-21 and show that protection of pdcd4b from miR-21 binding results in failure of AV development. In vitro experiments using human pulmonic valve endothelial cells demonstrate that miR-21 overexpression augments endothelial cell migration. PDCD4 knockdown alone was sufficient to enhance endothelial cell migration. These results demonstrate that miR-21 plays a necessary role in cardiac valvulogenesis, in large part due to an obligatory downregulation of PDCD4.
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Kolpa
authors.forename: David S
authors.initials: DS
authors.lastname: Peal
authors.forename: Stacey N
authors.initials: SN
authors.lastname: Lynch
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Giokas
authors.forename: Shibnath
authors.initials: S
authors.lastname: Ghatak
authors.forename: Suniti
authors.initials: S
authors.lastname: Misra
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
authors.forename: Calum A
authors.initials: CA
authors.lastname: Macrae
authors.forename: Roger R
authors.initials: RR
authors.lastname: Markwald
authors.forename: Patrick
authors.initials: P
authors.lastname: Ellinor
authors.forename: Joyce
authors.initials: J
authors.lastname: Bischoff
authors.forename: David J
authors.initials: DJ
authors.lastname: Milan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002465:Cell Movement; D003433:Crosses, Genetic; D042783:Endothelial Cells / Q000166:cytology; D018507:Gene Expression Regulation, Developmental; D006351:Heart Valves / Q000196:embryology*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D013997:Time Factors; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; C585277:MIRN21 microRNA, zebrafish; D035683:MicroRNAs; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D029961:Zebrafish Proteins; C581874:pdcd4b protein, zebrafish