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

Nicholas B Ang,Caroline Walsh,Peter F Hitchcock,Alfonso Saera-Vila,Ryan Thummel,Alon Kahana,Mikiko Nagashima,David R Hyde

doi:10.1371/journal.pone.0232308

Nicholas B Ang, Caroline Walsh + Show 6 more

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https://doi.org/10.1371/journal.pone.0232308

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Abstract

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.

Highlights

Epimorphic regeneration is the process of replacing ablated cells and tissues, which are functionally integrated into the mature organ
To determine the function of Midkine-a during fin regeneration, fins from wildtype and mdkami5001 were amputated and proliferation was evaluated in each using immunostaining for proliferating cell nuclear antigen (PCNA) and BrdU incorporation
The initial outgrowth of fins in the mdkami5001 was reduced in size (Fig 1A–1D), and the blastemal compartment contained significantly fewer PCNA- (Fig 1C–1F) and BrdU-positive cells (Fig 1G–1I)

Summary

Introduction

Epimorphic regeneration is the process of replacing ablated cells and tissues, which are functionally integrated into the mature organ. The abiding scientific interest in epimorphic regeneration is sustained by the striking dichotomy in the regenerative abilities between vertebrates, such as amphibians and teleost fish, and mammals [1,2]. Identifying the molecular mechanisms that govern epimorphic regeneration holds the promise of informing therapeutic approaches for treating injuries in humans. Zebrafish is an excellent model to study epimorphic regeneration.

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