title: Upregulation of leukemia inhibitory factor (LIF) during the early stage of optic nerve regeneration in zebrafish.
abstract: Fish retinal ganglion cells (RGCs) can regenerate their axons after optic nerve injury, whereas mammalian RGCs normally fail to do so. Interleukin 6 (IL-6)-type cytokines are involved in cell differentiation, proliferation, survival, and axon regrowth; thus, they may play a role in the regeneration of zebrafish RGCs after injury. In this study, we assessed the expression of IL-6-type cytokines and found that one of them, leukemia inhibitory factor (LIF), is upregulated in zebrafish RGCs at 3 days post-injury (dpi). We then demonstrated the activation of signal transducer and activator of transcription 3 (STAT3), a downstream target of LIF, at 3-5 dpi. To determine the function of LIF, we performed a LIF knockdown experiment using LIF-specific antisense morpholino oligonucleotides (LIF MOs). LIF MOs, which were introduced into zebrafish RGCs via a severed optic nerve, reduced the expression of LIF and abrogated the activation of STAT3 in RGCs after injury. These results suggest that upregulated LIF drives Janus kinase (Jak)/STAT3 signaling in zebrafish RGCs after nerve injury. In addition, the LIF knockdown impaired axon sprouting in retinal explant culture in vitro; reduced the expression of a regeneration-associated molecule, growth-associated protein 43 (GAP-43); and delayed functional recovery after optic nerve injury in vivo. In this study, we comprehensively demonstrate the beneficial role of LIF in optic nerve regeneration and functional recovery in adult zebrafish.
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan; Wellness Promotion Science Center, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogai
authors.affiliation: Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Kuwana
authors.affiliation: Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Hisano
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Nagashima
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan; Graduate School and Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Koriyama
authors.affiliation: Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Sugitani
authors.affiliation: Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mawatari
authors.affiliation: Department of Clinical Laboratory Science, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: Department of Molecular Neurobiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D004058:Diffusion; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D060172:Morpholinos / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D020221:Optic Nerve Injuries / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000534:rehabilitation; D020127:Recovery of Function / Q000502:physiology; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D046509:Tissue Culture Techniques; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D019922:GAP-43 Protein; D053605:Leukemia Inhibitory Factor; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D050796:STAT3 Transcription Factor; D029961:Zebrafish Proteins; C520573:m17 protein, zebrafish; C494089:stat3 protein, zebrafish; D053613:Janus Kinase 1