title: Haemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow-dependent expression of miR-21.
abstract: Heartbeat is required for normal development of the heart, and perturbation of intracardiac flow leads to morphological defects resembling congenital heart diseases. These observations implicate intracardiac haemodynamics in cardiogenesis, but the signalling cascades connecting physical forces, gene expression and morphogenesis are largely unknown. Here we use a zebrafish model to show that the microRNA, miR-21, is crucial for regulation of heart valve formation. Expression of miR-21 is rapidly switched on and off by blood flow. Vasoconstriction and increasing shear stress induce ectopic expression of miR-21 in the head vasculature and heart. Flow-dependent expression of mir-21 governs valvulogenesis by regulating the expression of the same targets as mouse/human miR-21 (sprouty, pdcd4, ptenb) and induces cell proliferation in the valve-forming endocardium at constrictions in the heart tube where shear stress is highest. We conclude that miR-21 is a central component of a flow-controlled mechanotransduction system in a physicogenetic regulatory loop.
authors.affiliation: Graduate School of Life Sciences, Tohoku University, 2-1-1 Katahira, Aoba, Sendai, Miyagi 980-8577, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Banjo
authors.forename: Janin
authors.initials: J
authors.lastname: Grajcarek
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshino
authors.forename: Hideto
authors.initials: H
authors.lastname: Osada
authors.forename: Kota Y
authors.initials: KY
authors.lastname: Miyasaka
authors.forename: Yasuyuki S
authors.initials: YS
authors.lastname: Kida
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ueki
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nagayama
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawakami
authors.forename: Takeo
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ogura
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001775:Blood Circulation / Q000187:drug effects / Q000502:physiology*; D002070:Butadienes / Q000494:pharmacology; D003931:Diacetyl / Q000031:analogs & derivatives / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D057809:HEK293 Cells; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism; D006439:Hemodynamics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D002070:Butadienes; C585277:MIRN21 microRNA, zebrafish; D035683:MicroRNAs; D060172:Morpholinos; D009570:Nitriles; D012333:RNA, Messenger; C113580:U 0126; D029961:Zebrafish Proteins; C004717:diacetylmonoxime; D003931:Diacetyl