Limb Development and Regeneration

TLDR

Pattern formation and growth control are causally linked in vertebrate limb development and regeneration. The study proposes that fibroblast intercalation generates a connective tissue scaffold that directs limb cell positioning and morphogenesis. Intercalation drives position‑specific growth, initiating, maintaining, and terminating limb development. Only fibroblasts carry positional cues for intercalation, and regenerative failure in higher vertebrates is linked to intercalation defects, underscoring the need to understand these mechanisms to stimulate limb regeneration.

Abstract

Experiments on developing and regenerating vertebrate limbs have led to the idea that pattern formation and growth control are causally linked. The mechanism by which position-specific growth occurs is termed intercalation, and evidence is presented that implicates intercalation in the initiation, maintenance and cessation of growth during limb formation. We conclude that among the variety of cell types present in limbs, only fibroblasts have been shown to possess the positional information necessary for intercalation. Hence we propose that the limb pattern is generated by intercalation between fibroblasts to give rise to a connective tissue scaffold, which in turn dictates the positioning and morphogenesis of all of the differentiated cell types of the limb. Finally, we review evidence that regenerative failure among higher vertebrates is linked to defects in the intrinsic cellular mechanisms of growth control (intercalation) and conclude that progress towards the goal of stimulating regenerative limb outgrowth in non-regenerating vertebrates will be contingent upon a better understanding of these intrinsic mechanisms.