title: Hyaluronic acid synthesis is required for zebrafish tail fin regeneration.
abstract: Using genome-wide transcriptional profiling and whole-mount expression analyses of zebrafish larvae, we have identified hyaluronan synthase 3 (has3) as an upregulated gene during caudal fin regeneration. has3 expression is induced in the wound epithelium within hours after tail amputation, and its onset and maintenance requires fibroblast growth factor, phosphoinositide 3-kinase, and transforming growth factor-ß signaling. Inhibition of hyaluronic acid (HA) synthesis by the small molecule 4-methylumbelliferone (4-MU) impairs tail regeneration in zebrafish larvae by preventing injury-induced cell proliferation. In addition, 4-MU reduces the expression of genes associated with wound epithelium and blastema function. Treatment with glycogen synthase kinase 3 inhibitors rescues 4-MU-induced defects in cell proliferation and tail regeneration, while restoring a subset of wound epithelium and blastema markers. Our findings demonstrate a role for HA biosynthesis in zebrafish tail regeneration and delineate its epistatic relationships with other regenerative processes.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Panetta
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Maya D
authors.initials: MD
authors.lastname: Talbott
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Alexander Y
authors.initials: AY
authors.lastname: Payumo
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Halluin
authors.affiliation: Department of Surgery, Stanford University School of Medicine, Stanford, California, United States of America.|Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America.|Department of Developmental Biology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: James K
authors.identifier: http://orcid.org/0000-0002-9220-8436
authors.initials: JK
authors.lastname: Chen
mesh_terms: D058500:Animal Fins / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004843:Epistasis, Genetic; D005786:Gene Expression Regulation / Q000187:drug effects; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000096:biosynthesis / Q000502:physiology*; D006923:Hymecromone / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000235:genetics; D015027:Zebrafish / Q000378:metabolism / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D029961:Zebrafish Proteins; D006923:Hymecromone; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases