Calcineurin controls proximodistal blastema polarity in zebrafish fin regeneration

Abstract

Planarian flatworms regenerate their heads and tails from anterior or posterior wounds and this regenerative blastema polarity is controlled by Wnt/β-catenin signaling. It is well known that a regeneration blastema of appendages of vertebrates such as fish and amphibians grows distally. However, it remains unclear whether a regeneration blastema in vertebrate appendages can grow proximally. Here, we show that a regeneration blastema in zebrafish fins can grow proximally along the proximodistal axis by calcineurin inhibition. We used fin excavation in adult zebrafish to observe unidirectional regeneration from the anterior cut edge (ACE) to the posterior cut edge (PCE) of the cavity and this unidirectional regeneration polarity occurs as the PCE fails to build blastemas. Furthermore, we found that calcineurin activities in the ACE were greater than in the PCE. Calcineurin inhibition induced PCE blastemas, and calcineurin hyperactivation suppressed fin regeneration. Collectively, these findings identify calcineurin as a molecular switch to specify the PCE blastema of the proximodistal axis and regeneration polarity in zebrafish fin.

Regenerative Polarity of the Fin Ray in Zebrafish Caudal Fin and Related Tissue Formation on the Cut Surface

“…In contrast to our results, a recent report by Cao et al [ 26 ] on fin hole regeneration did not mention the expression of regeneration-related genes at the distal margin of the hole. This is possibly due to the differences in experimental conditions; in their report, two fin ray rows were excised, but we excised one row.…”

“…This is possibly due to the differences in experimental conditions; in their report, two fin ray rows were excised, but we excised one row. In addition, the length of the hole prepared in our study was longer than that in their experiment [ 26 ]. Because the area of gene expression in the distal margin was restricted to a small area in our experiment, as mentioned above, the signals of gene expression may be unclear in other experimental conditions.…”

“…When a part of the caudal fin ray of the zebrafish is excised, the missing part regenerates from the remaining tissue at the proximal margin of the hole, but not in the opposite direction [ 3 , 25 ]. Although the mechanism of polarized regeneration of the fin ray is not well understood, opposite regeneration of the caudal fin has been reported in long fin ( lof ) mutants of zebrafish [ 26 ], and the calcineurin signaling pathway has been reported to be involved in the polarity of caudal fin regeneration [ 26 ]. These results suggest that opposite directional regeneration of the zebrafish caudal fin only occurs when there are specific genetic mutations present or under pharmacological conditions.…”

A calcineurin-mediated scaling mechanism that controls a K+-leak channel to regulate morphogen and growth factor transcription

“…A recent finding showed that calcineurin inhibition or increased activity of the voltagegated Kcnh2 channel (lof mutant) promotes regenerative outgrowth from the proximal side of a mid-fin excavation, a site that normally does not mount a regenerative outgrowth response (Cao et al, 2021). Our findings help explain how calcineurin-regulated and electrophysiological changes from potassium channels can lead to broader tissue organizing phenomena by showing the inductive effect that increasing K + conductance (and calcineurin's regulation of K + conductance) can have on a broad number of developmental pathways, which is important for coordinating the organized formation of tissues and organs.…”

Zebrafish as a Model for Germ Cell Regeneration

“…Zebrafish ( Danio rerio ) has remarkable regenerative capabilities and becomes one of the most widely used vertebrate models for regenerative studies. Zebrafish is capable of regenerating a range of tissues including fin ( Shibata et al, 2016 ; Cao et al, 2021 ), heart ( Poss et al, 2002 ), spinal cord ( Mokalled et al, 2016 ), brain ( Lucini et al, 2018 ), liver ( He et al, 2014 ), hair cells ( Thomas and Raible, 2019 ), kidney ( Reimschuessel, 2001 ), and retina ( Vihtelic and Hyde, 2000 ). Although regeneration studies mainly focus on these somatic tissues, recent studies about reproductive system regeneration attract much interest.…”