Sequential and opposing activities of Wnt and BMP coordinate zebrafish bone regeneration.
Zebrafish fully regenerate lost bone, including after fin amputation, through a process mediated by dedifferentiated, lineage-restricted osteoblasts. Mechanisms controlling the osteoblast regenerative program from its initiation through reossification are poorly understood. We show that fin amputation induces a Wnt/β-catenin-dependent epithelial to mesenchymal transformation (EMT) of osteoblasts in order to generate proliferative Runx2(+) preosteoblasts. Localized Wnt/β-catenin signaling maintains this progenitor population toward the distal tip of the regenerative blastema. As they become proximally displaced, preosteoblasts upregulate sp7 and subsequently mature into re-epithelialized Runx2(-)/sp7(+) osteoblasts that extend preexisting bone. Autocrine bone morphogenetic protein (BMP) signaling promotes osteoblast differentiation by activating sp7 expression and counters Wnt by inducing Dickkopf-related Wnt antagonists. As such, opposing activities of Wnt and BMP coordinate the simultaneous demand for growth and differentiation during bone regeneration. This hierarchical signaling network model provides a conceptual framework for understanding innate bone repair and regeneration mechanisms and rationally designing regenerative therapeutics.
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA. Electronic address: sstewart@molbio.uoregon.edu.
Scott
S
Stewart
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Alan W
AW
Gomez
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Benjamin E
BE
Armstrong
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
Astra
A
Henner
Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA; Department of Biology, University of Oregon, Eugene, OR 97403, USA. Electronic address: kryn@uoregon.edu.
Kryn
K
Stankunas
D058500:Animal Fins / Q000166:cytology / Q000502:physiology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001861:Bone Regeneration / Q000235:genetics / Q000502:physiology*; D054337:Cell Dedifferentiation / Q000235:genetics; D019070:Cell Lineage; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005786:Gene Expression Regulation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin