Midkine-a functions as a universal regulator of proliferation during epimorphic regeneration in adult zebrafish

• Published in: PloS one 2020-06, Vol.15 (6), p.e0232308
• Main Authors: Ang, Nicholas B, Saera-Vila, Alfonso, Walsh, Caroline, Hitchcock, Peter F, Kahana, Alon, Thummel, Ryan, Nagashima, Mikiko
• Format: Article
• Language: English
• Subjects: Ablation; Amputation; Analysis; Animal Fins - physiology; Animals; Animals, Genetically Modified - metabolism; Apoptosis; Biological activity; Biology and Life Sciences; Cell cycle; Cell Differentiation; Cell Proliferation; Cell regulation; Cells (biology); Cytokines; Danio rerio; Growth factors; Injuries; Medicine and Health Sciences; Midkine; Midkine - genetics; Midkine - metabolism; Molecular modelling; Muscles; Mutagenesis; Mutants; Nervous system; Neuroglia - cytology; Neuroglia - metabolism; Oculomotor Muscles - physiology; Photoreceptors; Physiological aspects; Progenitor cells; Regeneration; Regeneration (Biology); Regeneration - physiology; Research and Analysis Methods; Retina; Retinal Neurons - physiology; Social Sciences; Stem cells; Tissues; Vertebrates; Zebrafish; Zebrafish - metabolism; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0232308

Zebrafish have the ability to regenerate damaged cells and tissues by activating quiescent stem and progenitor cells or reprogramming differentiated cells into regeneration-competent precursors. Proliferation among the cells that will functionally restore injured tissues is a fundamental biological process underlying regeneration. Midkine-a is a cytokine growth factor, whose expression is strongly induced by injury in a variety of tissues across a range of vertebrate classes. Using a zebrafish Midkine-a loss of function mutant, we evaluated regeneration of caudal fin, extraocular muscle and retinal neurons to investigate the function of Midkine-a during epimorphic regeneration. In wildtype zebrafish, injury among these tissues induces robust proliferation and rapid regeneration. In Midkine-a mutants, the initial proliferation in each of these tissues is significantly diminished or absent. Regeneration of the caudal fin and extraocular muscle is delayed; regeneration of the retina is nearly completely absent. These data demonstrate that Midkine-a is universally required in the signaling pathways that convert tissue injury into the initial burst of cell proliferation. Further, these data highlight differences in the molecular mechanisms that regulate epimorphic regeneration in zebrafish.