title: Autophagy regulates cytoplasmic remodeling during cell reprogramming in a zebrafish model of muscle regeneration.
abstract: Cell identity involves both selective gene activity and specialization of cytoplasmic architecture and protein machinery. Similarly, reprogramming differentiated cells requires both genetic program alterations and remodeling of the cellular architecture. While changes in genetic and epigenetic programs have been well documented in dedifferentiating cells, the pathways responsible for remodeling the cellular architecture and eliminating specialized protein complexes are not as well understood. Here, we utilize a zebrafish model of adult muscle regeneration to study cytoplasmic remodeling during cell dedifferentiation. We describe activation of autophagy early in the regenerative response to muscle injury, while blocking autophagy using chloroquine or Atg5 and Becn1 knockdown reduced the rate of regeneration with accumulation of sarcomeric and nuclear debris. We further identify Casp3/caspase 3 as a candidate mediator of cellular reprogramming and Fgf signaling as an important activator of autophagy in dedifferentiating myocytes. We conclude that autophagy plays a critical role in cell reprogramming by regulating cytoplasmic remodeling, facilitating the transition to a less differentiated cell identity.
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Kellogg Eye Center, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Saera-Vila
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Kellogg Eye Center, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Kish
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Kellogg Eye Center, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Ke'ale W
authors.initials: KW
authors.lastname: Louie
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Kellogg Eye Center, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Grzegorski
authors.affiliation: b Life Sciences Institute, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Klionsky
authors.affiliation: a Department of Ophthalmology and Visual Sciences , Kellogg Eye Center, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Kahana
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy; D065150:Cellular Reprogramming; D003593:Cytoplasm / Q000378:metabolism*; D004734:Energy Metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism; D008954:Models, Biological; D009801:Oculomotor Muscles / Q000502:physiology*; D012038:Regeneration; D015854:Up-Regulation; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*
chemical_list: D005346:Fibroblast Growth Factors
keywords: Atg5; autolysosome; dedifferentiation; electron microscopy; extraocular muscle; regeneration; reprogramming; stem cell; strabismus; zebrafish