Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin

Jacob M Daane,Charles W Higdon,Ina Rothenberg,Stephen L Johnson,Guiscard Seebohm,Jennifer Lanni,Matthew P Harris

doi:10.1038/s41598-018-28450-6

Abstract

The establishment of relative size of organs and structures is paramount for attaining final form and function of an organism. Importantly, variation in the proportions of structures frequently underlies adaptive change in morphology in evolution and maybe a common mechanism underlying selection. However, the mechanism by which growth is integrated within tissues during development to achieve proper proportionality is poorly understood. We have shown that signaling by potassium channels mediates coordinated size regulation in zebrafish fins. Recently, calcineurin inhibitors were shown to elicit changes in zebrafish fin allometry as well. Here, we identify the potassium channel kcnk5b as a key player in integrating calcineurin’s growth effects, in part through regulation of the cytoplasmic C-terminus of the channel. We propose that the interaction between Kcnk5b and calcineurin acts as a signaling node to regulate allometric growth. Importantly, we find that this regulation is epistatic to inherent mechanisms instructing overall size as inhibition of calcineurin is able to bypass genetic instruction of size as seen in sof and wild-type fins, however, it is not sufficient to re-specify positional memory of size of the fin. These findings integrate classic signaling mediators such as calcineurin with ion channel function in the regulation of size and proportion during growth.

Highlights

The establishment of relative proportion of structures and organs is essential for the normal physiology and function of an organism
A common mechanism for the establishment of organ size and the relative proportions of structures is through differential sensitivity of organs to a systemic growth signal such as insulin-like growth factors (IGF) or growth hormone (GH)[5,6]
Analysis of the patterning and gene expression profiles in overgrown fins treated with FK506 led Kujawski and colleagues to suggest that positional information of the fin was altered by calcineurin inhibition

Summary

Introduction

The establishment of relative proportion of structures and organs is essential for the normal physiology and function of an organism. A key advance in our understanding differential growth stems from the work of D’Arcy Thompson and his efforts to define the underlying rules of coordinated transformations in form[2] This foundational work was leveraged by Huxley and Teissier who formalized scaling relationships between structures within organisms as a power law that details the relative proportion of structures[3,4]. Supporting a role for ion regulation in establishing proportion, the shortfin (sof) mutant has been mapped back to mutations in the gap junction connexin[43] (cx43/gja1)[18,25] Though both gap junctions and potassium channels have important roles in physiology and cell biology, these initial findings in the zebrafish fin are surprising in that they uncover a specific role for local bioelectric signaling in the regulation and coordination of growth. Activation of calcineurin triggers a proximal-like growth program that leads to enhanced proliferation to re-specify larger fin sizes[26]

Methods

Results

Conclusion