longfin causes cis-ectopic expression of the kcnh2a ether-a-go-go K+ channel to autonomously prolong fin outgrowth

ABSTRACT Organs stop growing to achieve the size and shape characteristic of the species and in scale with the animal’s body. Likewise, regenerating organs sense injury extents to instruct appropriate replacement growth. Fish fins exemplify both phenomena through their tremendous diversity of form and remarkably robust regeneration. The classic zebrafish mutant longfin develops and regenerates dramatically elongated fins and underlying bony ray skeleton. Here, we show longfin mutant chromosome 2 overexpresses kcnh2a, a voltage-gated potassium channel related to human ether-a-go-go. Genetic disruption of kcnh2a in cis rescues the dominant longfin eponymous phenotype, indicating longfin is a regulatory allele of kcnh2a. We find regenerative fin overgrowth in longfin is characterized by a prolonged outgrowth period rather than increased maximal growth rate. Accordingly, small molecule inhibition of Kcnh2a during late but not early stages of fin regeneration fully suppresses longfin fin overgrowth. Blastula stage transplantations show longfin-expressed kcnh2a acts tissue autonomously in the fin intra-ray mesenchymal lineage, where it is concordantly ectopically expressed. We use temporal delivery of FK506 to show the Ca2+-dependent phosphatase calcineurin likewise entirely acts late in regeneration to attenuate the fin outgrowth period. Epistasis experiments suggest longfin-expressed Kcnh2a inhibits calcineurin signaling to supersede endogenous growth cessation signals. Our results indicate how ion signaling within a growth-determining mesenchyme-lineage controls fin size and morphological variation by tuning outgrowth periods rather than altering positional information.