title: The SHH/Gli pathway is reactivated in reactive glia and drives proliferation in response to neurodegeneration-induced lesions.
abstract: In response to neurodegeneration, the adult mammalian brain activates a cellular cascade that results in reactive astrogliosis and microgliosis. The mechanism through which astrocytes become reactive and the physiological consequences of their activation in response to neurodegeneration is complex. While the activation and proliferation of astrocytes has been shown to occur during massive neuronal cell death, the functional relationship between these two events has not been clearly elucidated. Here we show that in response to kainic acid- (KA) induced neurodegeneration, the mitogen sonic hedgehog (SHH) is upregulated in reactive astrocytes. SHH activity peaks at 7 days and is accompanied by increased Gli activity and elevated proliferation in several cell types. To determine the functional role of SHH-Gli signaling following KA lesions, we used a pharmacological approach to show that SHH secreted by astrocytes drives the activation and proliferation of astrocytes and microglia. The consequences of SHH-Gli signaling in KA-induced lesions appear to be independent of the severity of neurodegeneration.
authors.affiliation: Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York; The Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Pitter
authors.forename: Ilaria
authors.initials: I
authors.lastname: Tamagno
authors.forename: Xi
authors.initials: X
authors.lastname: Feng
authors.forename: Kaushik
authors.initials: K
authors.lastname: Ghosal
authors.forename: Nduka
authors.initials: N
authors.lastname: Amankulor
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Dolores
authors.initials: D
authors.lastname: Hambardzumyan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002491:Central Nervous System Agents; D004195:Disease Models, Animal; D053823:Hedgehog Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D007608:Kainic Acid; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000473:pathology / Q000503:physiopathology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D012640:Seizures / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: D002491:Central Nervous System Agents; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; C465570:Shh protein, mouse; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D007608:Kainic Acid; C000541:cyclopamine
keywords: Gli; Sonic Hedgehog; astrogliosis; microgliosis; neurodegeneration