title: The stat3/socs3a pathway is a key regulator of hair cell regeneration in zebrafish. [corrected].
abstract: All nonmammalian vertebrates studied can regenerate inner ear mechanosensory receptors (i.e., hair cells) (Corwin and Cotanche, 1988; Lombarte et al., 1993; Baird et al., 1996), but mammals possess only a very limited capacity for regeneration after birth (Roberson and Rubel, 1994). As a result, mammals experience permanent deficiencies in hearing and balance once their inner ear hair cells are lost. The mechanisms of hair cell regeneration are poorly understood. Because the inner ear sensory epithelium is highly conserved in all vertebrates (Fritzsch et al., 2007), we chose to study hair cell regeneration mechanism in adult zebrafish, hoping the results would be transferrable to inducing hair cell regeneration in mammals. We defined the comprehensive network of genes involved in hair cell regeneration in the inner ear of adult zebrafish with the powerful transcriptional profiling technique digital gene expression, which leverages the power of next-generation sequencing ('t Hoen et al., 2008). We also identified a key pathway, stat3/socs3, and demonstrated its role in promoting hair cell regeneration through stem cell activation, cell division, and differentiation. In addition, transient pharmacological inhibition of stat3 signaling accelerated hair cell regeneration without overproducing cells. Taking other published datasets into account (Sano et al., 1999; Schebesta et al., 2006; Dierssen et al., 2008; Riehle et al., 2008; Zhu et al., 2008; Qin et al., 2009), we propose that the stat3/socs3 pathway is a key response in all tissue regeneration and thus an important therapeutic target for a broad application in tissue repair and injury healing.
authors.affiliation: Genome Technology Branch, and Inherited Disease Research Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Liang
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.forename: Gabriel
authors.initials: G
authors.lastname: Renaud
authors.forename: Tyra G
authors.initials: TG
authors.lastname: Wolfsberg
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Wilson
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Burgess
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D016009:Chi-Square Distribution; D019327:Copper Sulfate / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000502:physiology*; D007814:Larva; D053403:Lateral Line System / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D008297:Male; D060172:Morpholinos / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics; D009622:Noise / Q000009:adverse effects; D012333:RNA, Messenger / Q000008:administration & dosage; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D060172:Morpholinos; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D029961:Zebrafish Proteins; C540940:socs3a protein, zebrafish; C494089:stat3 protein, zebrafish; D049452:Green Fluorescent Proteins; D001973:Bromodeoxyuridine; D019327:Copper Sulfate