title: JNK controls the onset of mitosis in planarian stem cells and triggers apoptotic cell death required for regeneration and remodeling.
abstract: Regeneration of lost tissues depends on the precise interpretation of molecular signals that control and coordinate the onset of proliferation, cellular differentiation and cell death. However, the nature of those molecular signals and the mechanisms that integrate the cellular responses remain largely unknown. The planarian flatworm is a unique model in which regeneration and tissue renewal can be comprehensively studied in vivo. The presence of a population of adult pluripotent stem cells combined with the ability to decode signaling after wounding enable planarians to regenerate a complete, correctly proportioned animal within a few days after any kind of amputation, and to adapt their size to nutritional changes without compromising functionality. Here, we demonstrate that the stress-activated c-jun-NH2-kinase (JNK) links wound-induced apoptosis to the stem cell response during planarian regeneration. We show that JNK modulates the expression of wound-related genes, triggers apoptosis and attenuates the onset of mitosis in stem cells specifically after tissue loss. Furthermore, in pre-existing body regions, JNK activity is required to establish a positive balance between cell death and stem cell proliferation to enable tissue renewal, remodeling and the maintenance of proportionality. During homeostatic degrowth, JNK RNAi blocks apoptosis, resulting in impaired organ remodeling and rescaling. Our findings indicate that JNK-dependent apoptotic cell death is crucial to coordinate tissue renewal and remodeling required to regenerate and to maintain a correctly proportioned animal. Hence, JNK might act as a hub, translating wound signals into apoptotic cell death, controlled stem cell proliferation and differentiation, all of which are required to coordinate regeneration and tissue renewal.
authors.affiliation: Department of Genetics and Institute of Biomedicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Almuedo-Castillo
authors.affiliation: Department of Genetics and Institute of Biomedicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Xenia
authors.initials: X
authors.lastname: Crespo-Yanez
authors.affiliation: Department of Genetics and Institute of Biomedicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Xenia
authors.initials: X
authors.lastname: Crespo
authors.affiliation: Max Planck Research Group Stem Cells and Regeneration, Max Planck Institute for Molecular Biomedicine, Münster, Germany; Faculty of Medicine, University of Münster, Münster, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Seebeck
authors.affiliation: Max Planck Research Group Stem Cells and Regeneration, Max Planck Institute for Molecular Biomedicine, Münster, Germany; Faculty of Medicine, University of Münster, Münster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Bartscherer
authors.affiliation: Department of Genetics and Institute of Biomedicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Emili
authors.initials: E
authors.lastname: Salò
authors.affiliation: Department of Genetics and Institute of Biomedicine, University of Barcelona, Barcelona, Catalonia, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Adell
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D019521:Body Patterning / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics*; D008938:Mitosis; D010932:Planarians / Q000166:cytology / Q000235:genetics*; D039904:Pluripotent Stem Cells / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012038:Regeneration; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D044767:Ubiquitin-Protein Ligases; D048031:JNK Mitogen-Activated Protein Kinases