Fgf signaling instructs position-dependent growth rate during zebrafish fin regeneration

TLDR

Appendage regeneration relies on positional memory and a proximodistal gradient that governs tissue amount and growth rate, with proximal amputations regenerating faster than distal ones, yet the underlying molecular mechanisms remain unknown. The study aims to characterize how growth rates vary with position during zebrafish caudal fin regeneration. Transgenic zebrafish with controllable Fgf receptor activity were used to test whether positional differences in Fgf signaling drive blastemal function. We found that Fgf signaling levels strictly regulate target gene expression, blastemal proliferation, and growth rate, establishing position-dependent blastemal properties that determine regenerative speed.

Abstract

During appendage regeneration in urodeles and teleosts, tissue replacement is precisely regulated such that only the appropriate structures are recovered, a phenomenon referred to as positional memory. It is believed that there exists, or is quickly established after amputation, a dynamic gradient of positional information along the proximodistal (PD) axis of the appendage that assigns region-specific instructions to injured tissue. These instructions specify the amount of tissue to regenerate, as well as the rate at which regenerative growth is to occur. A striking theme among many species is that the rate of regeneration is more rapid in proximally amputated appendages compared with distal amputations. However, the underlying molecular regulation is unclear. Here, we identify position-dependent differences in the rate of growth during zebrafish caudal fin regeneration. These growth rates correlate with position-dependent differences in blastemal length, mitotic index and expression of the Fgf target genes mkp3, sef and spry4. To address whether PD differences in amounts of Fgf signaling are responsible for position-dependent blastemal function, we have generated transgenic fish in which Fgf receptor activity can be experimentally manipulated. We find that the level of Fgf signaling exhibits strict control over target gene expression, blastemal proliferation and regenerative growth rate. Our results demonstrate that Fgf signaling defines position-dependent blastemal properties and growth rates for the regenerating zebrafish appendage.