title: Acute retinal injury and the relationship between nerve growth factor, Notch1 transcription and short-lived dedifferentiation transient changes of mammalian Müller cells.
abstract: Our aim is to define related molecular events on how dormant Müller glia cells re-enter the cell cycle, proliferate and produce new retinal neurons from initial injury to glial scar formation. Sodium iodate (NaIO3) was used to induce acute retinal injury. Long-Evans rats were administered with NaIO3 or phosphate-buffered saline by intraperitoneal injection. The proliferation, dedifferentiation and neurogenesis of Müller cells were analyzed by double-labeled fluorescence immunohistochemistry with primary antibodies - against Müller cells and specific cell markers. Possible molecules that limit the regenerative potential of Müller cells were also determined by immunofluorescence staining, quantitative RT-PCR, protein array, ELISA and Western blot. In the first 3-7days after NaIO3 administration, Müller cells were activated and underwent a fate switch, including transient proliferation, dedifferentiation and neurogenesis. Nerve growth factor (NGF) signaling concomitantly increased with the downregulation of p27(Kip1) in Müller cells, which may promote Müller cells to re-enter the cell cycle. The transient increase of NGF signaling and the transient decrease of Notch signaling inhibited Hes1, which might enhance the neuronal differentiation of dedifferentiated Müller cells and suppress gliosis. Upregulated Notch and decreased NGF expressions limit dedifferentiation and neurogenesis, but induces retinal Müller cell gliosis at a later stage. We conclude that transient NGF upregulation and Notch1 downregulation may activate the transient proliferation, dedifferentiation and neurogenesis of Müller cells during NaIO3-induced acute retinal injury; which could be a therapeutic target for overcoming Müller cell gliosis. Such therapy could be potentially used for treating retinal-related diseases.
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jian
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.
authors.forename: Zui
authors.initials: Z
authors.lastname: Tao
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: yaochenli-2004@163.com.
authors.forename: Yaochen
authors.initials: Y
authors.lastname: Li
authors.affiliation: Southwest Hospital/Southwest Eye Hospital, Third Military Medical University, Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China. Electronic address: qinzyin@aliyun.com.
authors.forename: Zheng Qin
authors.initials: ZQ
authors.lastname: Yin
mesh_terms: D000208:Acute Disease; D000818:Animals; D054337:Cell Dedifferentiation / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D063928:Ependymoglial Cells / Q000502:physiology*; D020932:Nerve Growth Factor / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000502:physiology*; D012160:Retina / Q000166:cytology / Q000293:injuries*; D012164:Retinal Diseases / Q000503:physiopathology; D055351:Retinal Neurons / Q000502:physiology*
chemical_list: C497763:Notch1 protein, rat; D051881:Receptor, Notch1; D020932:Nerve Growth Factor
keywords: Acute retinal injury; Dedifferentiation; Gliosis; Müller cell; Nerve growth factor; Notch signaling pathway