title: Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2.
abstract: Müller glia are the primary glial subtype in the retina and perform a wide range of physiological tasks in support of retinal function, but little is known about the transcriptional network that maintains these cells in their differentiated state. We report that selective deletion of the LIM homeodomain transcription factor Lhx2 from mature Müller glia leads to the induction of reactive retinal gliosis in the absence of injury. Furthermore, Lhx2 expression is also down-regulated in Prph2(Rd2/Rd2) animals immediately before the onset of reactive gliosis. Analysis of conditional Lhx2 knockouts showed that gliosis was hypertrophic but not proliferative. Aging of experimental animals demonstrated that constitutive reactive gliosis induced by deletion of Lhx2 reduced rates of ongoing apoptosis and compromised both rod and cone photoreceptor function. Additionally, these animals showed a dramatically reduced ability to induce expression of secreted neuroprotective factors and displayed enhanced rates of apoptosis in light-damage assays. We provide in vivo evidence that Lhx2 actively maintains mature Müller glia in a nonreactive state, with loss of function initiating a specific program of nonproliferative hypertrophic gliosis.
authors.affiliation: Departments of Neuroscience, Center for High-Throughput Biology, and Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: de Melo
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Miki
authors.forename: Amir
authors.initials: A
authors.lastname: Rattner
authors.forename: Phil
authors.initials: P
authors.lastname: Smallwood
authors.forename: Cristina
authors.initials: C
authors.lastname: Zibetti
authors.forename: Karla
authors.initials: K
authors.lastname: Hirokawa
authors.forename: Edwin S
authors.initials: ES
authors.lastname: Monuki
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.forename: Seth
authors.initials: S
authors.lastname: Blackshaw
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D005786:Gene Expression Regulation; D005911:Gliosis / Q000235:genetics / Q000473:pathology*; D060850:LIM-Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D008027:Light; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D017434:Protein Structure, Tertiary; D012160:Retina / Q000473:pathology* / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D060850:LIM-Homeodomain Proteins; C489784:Lhx2 protein, mouse; D014157:Transcription Factors; D013629:Tamoxifen