title: Dynamic microRNA-101a and Fosab expression controls zebrafish heart regeneration.
abstract: Cardiovascular disease is the leading cause of morbidity and mortality in the Western world owing to the limited regenerative capacity of the mammalian cardiovascular system. In lieu of new muscle synthesis, the human heart replaces necrotic tissue with deposition of a noncontractile scar. By contrast, the adult zebrafish is endowed with a remarkable regenerative capacity, capable of de novo cardiomyocyte (CM) creation and scar tissue removal when challenged with an acute injury. In these studies, we examined the contributions of the dynamically regulated microRNA miR-101a during adult zebrafish heart regeneration. We demonstrate that miR-101a expression is rapidly depleted within 3 days post-amputation (dpa) but is highly upregulated by 7-14 dpa, before returning to uninjured levels at the completion of the regenerative process. Employing heat-inducible transgenic strains and antisense oligonucleotides, we demonstrate that decreases in miR-101a levels at the onset of cardiac injury enhanced CM proliferation. Interestingly, prolonged suppression of miR-101a activity stimulates new muscle synthesis but with defects in scar tissue clearance. Upregulation of miR-101a expression between 7 and 14 dpa is essential to stimulate removal of the scar. Through a series of studies, we identified the proto-oncogene fosab (cfos) as a potent miR-101a target gene, stimulator of CM proliferation, and inhibitor of scar tissue removal. Importantly, combinatorial depletion of fosab and miR-101a activity rescued defects in scar tissue clearance mediated by miR-101a inhibition alone. In summation, our studies indicate that the precise temporal modulation of the miR-101a/fosab genetic axis is crucial for coordinating CM proliferation and scar tissue removal during zebrafish heart regeneration.
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, USA Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Beauchemin
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Smith
authors.affiliation: Kathryn W. Davis Center for Regenerative Biology and Medicine, Mount Desert Island Biological Laboratory, Salisbury Cove, ME 04672, USA Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA vyin@mdibl.org.
authors.forename: Viravuth P
authors.initials: VP
authors.lastname: Yin
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002319:Cardiovascular System; D049109:Cell Proliferation; D002921:Cicatrix / Q000473:pathology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000166:cytology; D009336:Necrosis; D016376:Oligonucleotides, Antisense / Q000235:genetics; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics* / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology; D013997:Time Factors; D015027:Zebrafish / Q000254:growth & development*; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: C000715470:MAS1 protein, human; C000607899:MIRN101a, zebrafish; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D029961:Zebrafish Proteins; D049452:Green Fluorescent Proteins
keywords: Cardiomyocyte proliferation; Fosab; Heart regeneration; MicroRNA-101a; Scarring; Zebrafish