Transpositional scaling and niche transitions restore organ size and shape during zebrafish fin regeneration

ABSTRACT Adult fish fins regenerate to their original size and shape regardless of the nature or position of the injury. Spallanzani, Broussonet and Morgan initiated the pursuit of this scaling mystery of appendage regeneration in the 17th and 18th centuries. They and later researchers found the rate of regeneration initially correlates with the amount of tissue removed and then progressively decreases until outgrowth stops as the appendage’s form is restored. Prevailing models speculate that appendage cells harbor positional identities that instruct differential outgrowth after injury. We revisited Morgan’s fin resection experiments using the zebrafish model and show that differential Wnt production by distal niche cell populations determines the extent of regeneration. We identify Dachshund transcription factors as niche markers and show that the niche forms from intra-ray mesenchyme that populates the inside of the cylindrical and progressively tapered fin rays. The niche, and consequently Wnt, steadily dissipates as regeneration proceeds; once exhausted, growth stops. Supported by mathematical modeling, we show longfint2 zebrafish regenerate exceptionally long fins due to a broken niche “countdown timer”. We conclude that regenerated fin size is dictated by the amount of niche formed upon damage – which is simply dependent on the availability of intra-ray mesenchyme defined by bone girth at the injury site. This “transpositional scaling” model contends mesenchyme-niche state transitions and self-restoring skeletal geometry, not individual cell memories, determine a regenerated fin’s size and shape. One Sentence Summary Skeletal geometry provides the positional information for restoring organ size during appendage regeneration.