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 Muller glia cells re-enter the cell cycle, proliferate and produce new retinal neurons from initial injury to glial scar formation. Sodium iodate (NaIO 3 ) was used to induce acute retinal injury. Long-Evans rats were administered with NaIO 3 or phosphate-buffered saline by intraperitoneal injection. The proliferation, dedifferentiation and neurogenesis of Muller cells were analyzed by double-labeled fluorescence immunohistochemistry with primary antibodies – against Muller cells and specific cell markers. Possible molecules that limit the regenerative potential of Muller cells were also determined by immunofluorescence staining, quantitative RT-PCR, protein array, ELISA and Western blot. In the first 3–7 days after NaIO 3 administration, Muller 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 Muller cells, which may promote Muller 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 Muller cells and suppress gliosis. Upregulated Notch and decreased NGF expressions limit dedifferentiation and neurogenesis, but induces retinal Muller cell gliosis at a later stage. We conclude that transient NGF upregulation and Notch1 downregulation may activate the transient proliferation, dedifferentiation and neurogenesis of Muller cells during NaIO 3 -induced acute retinal injury; which could be a therapeutic target for overcoming Muller cell gliosis. Such therapy could be potentially used for treating retinal-related diseases.