title: Loss of Shp2-mediated mitogen-activated protein kinase signaling in Muller glial cells results in retinal degeneration.
abstract: Extensive studies have identified many growth factors and intracellular pathways that can promote neuronal survival after retinal injury, but the intrinsic survival mechanisms in the normal retina are poorly understood. Here we report that genetic ablation of Shp2 (Ptpn11) protein phosphatase resulted in progressive apoptosis of all retinal cell types. Loss of Shp2 specifically disrupted extracellular signal-regulated kinase (ERK) signaling in Müller cells, leading to Stat3 activation in photoreceptors. However, neither inactivation of Stat3 nor stimulation of AKT signaling could ameliorate the Shp2 retinal degeneration. Instead, constitutively activated Kras signaling not only rescued the retinal cell numbers in the Shp2 mutant but also functionally improved the electroretinogram recording (ERG). These results suggest that Shp2-mediated Ras-mitogen-activated protein kinase (Ras-MAPK) signaling plays a critical role in Müller cell maturation and function, which is necessary for the survival of retinal neurons.
authors.affiliation: Department of Medical and Molecular Genetics, Stark Neuroscience Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Cai
authors.forename: David L
authors.initials: DL
authors.lastname: Simons
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Fu
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Wu
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival; D004596:Electroretinography; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D051059:PTEN Phosphohydrolase; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins