Bone morphogenetic protein signaling promotes morphogenesis of blood vessels, wound epidermis, and actinotrichia during fin regeneration in zebrafish

FASEB J. 2015 Oct;29(10):4299-312. doi: 10.1096/fj.15-272955. Epub 2015 Jul 6.


Zebrafish fin regeneration involves initial formation of the wound epidermis and the blastema, followed by tissue morphogenesis. The mechanisms coordinating differentiation of distinct tissues of the regenerate are poorly understood. Here, we applied pharmacologic and transgenic approaches to address the role of bone morphogenetic protein (BMP) signaling during fin restoration. To map the BMP transcriptional activity, we analyzed the expression of the evolutionarily conserved direct phospho-Smad1 target gene, id1, and its homologs id2a and id3. This analysis revealed the BMP activity in the distal blastema, wound epidermis, osteoblasts, and blood vessels of the regenerate. Blocking the BMP function with a selective chemical inhibitor of BMP type I receptors, DMH1, suppressed id1 and id3 expression and arrested regeneration after blastema formation. We identified several previously uncharacterized functions of BMP during fin regeneration. Specifically, BMP signaling is required for remodeling of plexus into structured blood vessels in the rapidly growing regenerate. It organizes the wound epithelium by triggering wnt5b expression and promoting Collagen XIV-A deposition into the basement membrane. BMP represents the first known signaling that induces actinotrichia formation in the regenerate. Our data reveal a multifaceted role of BMP for coordinated morphogenesis of distinct tissues during regeneration of a complex vertebrate appendage.

Keywords: blastemal; regenerative angiogenesis; wound epithelium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Fins / metabolism*
  • Animal Fins / physiopathology
  • Animal Fins / surgery
  • Animals
  • Animals, Genetically Modified
  • Blood Vessels / growth & development
  • Blood Vessels / metabolism*
  • Bone Morphogenetic Proteins / antagonists & inhibitors
  • Bone Morphogenetic Proteins / genetics*
  • Bone Morphogenetic Proteins / metabolism
  • Collagen / genetics
  • Collagen / metabolism
  • Epidermis / injuries
  • Epidermis / metabolism*
  • Epidermis / physiopathology
  • Gene Expression Regulation, Developmental / drug effects
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • In Situ Hybridization
  • Inhibitor of Differentiation Protein 1 / genetics
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Morphogenesis / genetics
  • Pyrazoles / pharmacology
  • Quinolines / pharmacology
  • Regeneration / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Zebrafish / genetics*
  • Zebrafish / metabolism
  • Zebrafish / physiology
  • Zebrafish Proteins / genetics*
  • Zebrafish Proteins / metabolism


  • Bone Morphogenetic Proteins
  • DMH1 compound
  • Inhibitor of Differentiation Protein 1
  • Pyrazoles
  • Quinolines
  • Zebrafish Proteins
  • col14a1a protein, zebrafish
  • Green Fluorescent Proteins
  • Collagen