title: Injury-dependent Müller glia and ganglion cell reprogramming during tissue regeneration requires Apobec2a and Apobec2b.
abstract: Unlike mammals, adult zebrafish are able to regenerate multiple tissues including those of the CNS. In the zebrafish retina, injury stimulates Müller glia dedifferentiation into a multipotent retinal progenitor that is capable of regenerating all lost cell types. This dedifferentiation is driven by the reactivation of gene expression programs that share many characteristics with those that operate during early development. Although the mechanisms underlying the reactivation of these programs remain unknown, it is likely that changes in DNA methylation play a significant role. To begin investigating whether DNA demethylation may contribute to retina regeneration, we characterized the expression of genes associated with DNA demethylation in the uninjured and injured retina. We found that two cytidine deaminases (apobec2a and apobec2b) were expressed basally in the uninjured retina and that they were induced in proliferating, dedifferentiated Müller glia. The maximal induction of apobec2b required Ascl1a, but was independent of Lin28, and therefore defines an independent signaling pathway stemming from Ascl1a. Strikingly, when Apobec2a or Apobec2b was knocked down by antisense morpholino oligonucleotides, the proliferative response of Müller glia following injury was significantly reduced and injury-dependent induction of ascl1a and its target genes were inhibited, suggesting the presence of a regulatory feedback loop between Apobec proteins and ascl1a. Finally, Ascl1a, Apobec2a and Apobec2b were found to be essential for optic nerve regeneration. These data identify an essential role for Apobec proteins during retina and optic nerve regeneration and suggest DNA demethylation may underlie the reprogramming of cells to mount a regenerative response.
authors.affiliation: The Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor Michigan 48109, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Powell
authors.forename: Fairouz
authors.initials: F
authors.lastname: Elsaeidi
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D003564:Cytidine Deaminase / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D004625:Embryo, Nonmammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D066298:In Vitro Techniques; D008297:Male; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009457:Neuroglia / Q000502:physiology*; D009841:Oligonucleotides / Q000494:pharmacology; D009901:Optic Nerve Diseases / Q000150:complications; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012160:Retina / Q000293:injuries / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000502:physiology*; D013997:Time Factors; D014157:Transcription Factors; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D003564:Cytidine Deaminase; D051959:ELAV Proteins; D004791:Enzyme Inhibitors; D049452:Green Fluorescent Proteins; D009841:Oligonucleotides; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D014157:Transcription Factors; D029961:Zebrafish Proteins; C468127:Ascl1a protein, zebrafish