title: The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1.
abstract: miR-1is a small noncoding RNA molecule that modulates gene expression in heart and skeletal muscle. Loss ofDrosophila miR-1produces defects in somatic muscle and embryonic heart development, which have been partly attributed tomiR-1directly targeting Delta to decrease Notch signaling. Here, we show that overexpression ofmiR-1in the fly wing can paradoxically increase Notch activity independently of its effects on Delta. Analyses of potentialmiR-1targets revealed thatmiR-1directly regulates the 3'UTR of the E3 ubiquitin ligaseNedd4Analysis of embryonic and adult fly heart revealed that the Nedd4 protein regulates heart development inDrosophilaLarval fly hearts overexpressingmiR-1have profound defects in actin filament organization that are partially rescued by concurrent overexpression of Nedd4. These results indicate thatmiR-1and Nedd4 act together in the formation and actin-dependent patterning of the fly heart. Importantly, we have found that the biochemical and genetic relationship betweenmiR-1and the mammalian ortholog Nedd4-like (Nedd4l) is evolutionarily conserved in the mammalian heart, potentially indicating a role for Nedd4L in mammalian postnatal maturation. Thus,miR-1-mediated regulation of Nedd4/Nedd4L expression may serve to broadly modulate the trafficking or degradation of Nedd4/Nedd4L substrates in the heart.
authors.affiliation: Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Jun-Yi
authors.identifier: 0000-0002-4517-101X
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.|Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
authors.forename: Amy
authors.initials: A
authors.lastname: Heidersbach
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.|Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA.
authors.forename: Irfan S
authors.initials: IS
authors.lastname: Kathiriya
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.|Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA.
authors.forename: Bayardo I
authors.initials: BI
authors.lastname: Garay
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.|Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: Ivey
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.|Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
authors.forename: Deepak
authors.identifier: 0000-0002-3480-5953
authors.initials: D
authors.lastname: Srivastava
authors.affiliation: Children's National Medical Center, Washington, DC 20010, USA zhan@childrensnational.org isabelle.king@gladstone.ucsf.edu.
authors.forename: Zhe
authors.identifier: 0000-0002-5177-7798
authors.initials: Z
authors.lastname: Han
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA zhan@childrensnational.org isabelle.king@gladstone.ucsf.edu.|Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
authors.forename: Isabelle N
authors.identifier: 0000-0002-3182-7540
authors.initials: IN
authors.lastname: King
mesh_terms: D020413:3' Untranslated Regions; D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D019521:Body Patterning; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology; D035683:MicroRNAs / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D010641:Phenotype; D010766:Phosphorylation; D021381:Protein Transport; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014921:Wings, Animal / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D000199:Actins; D029721:Drosophila Proteins; C574927:MIRN1 microRNA, Drosophila; D035683:MicroRNAs; D051880:Receptors, Notch; D049452:Green Fluorescent Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000605755:Nedd4 protein, Drosophila; D044767:Ubiquitin-Protein Ligases
keywords: Heart; Nedd4; Nedd4-2; Nedd4L; miR-1