The Basic Helix-Loop-Helix Transcription Factor Olig2 Is Critical for Reactive Astrocyte Proliferation after Cortical Injury

Chen, Ying; Miles, Darryl K.; Hoang, ThaoNguyen; Shi, Jian; Hurlock, Edward C.; Kernie, Steven G.; Lü, Qing

doi:10.1523/jneurosci.3545-08.2008

Cited by 103 publications

(99 citation statements)

References 28 publications

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“…Although transcription factors such as Stat3, c-fos, cAMP-response element-binding protein (CREB), and Olig2 are known to be required to initiate reactive gliosis in response to extrinsic factors (23)(24)(25)(26)(27)(28), Lhx2 is unique because it regulates maintenance of the nonreactive state in Müller glia. Selective loss of function of Lhx2 in Müller glia does not compromise glial survival and likewise does not affect expression of glial markers such as P27 Kip1 and Cralbp.…”

Section: Discussionmentioning

confidence: 99%

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Melo

Miki

Rattner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.development | neurodegeneration M üller glia are the primary glial cell type in the vertebrate retina (1). The radial morphology of Müller glia creates a columnar matrix that maintains the laminar structure of the retina. Müller glia also perform a wide range of physiological tasks, including reuptake and metabolism of GABA and glutamate, water and ion homeostasis, and energetic support of photoreceptor cells (1, 2). Müller glia also participate in regeneration of the 11-cis retinal chromophore used by cone opsins (3, 4). Although the genetic regulation of Müller glial development has been extensively studied (5-8), virtually nothing is known about the intrinsic transcriptional network that maintains these cells, or any other astroglial subtype, in their terminally differentiated state.Like other astroglia, Müller glia can be induced to undergo reactive gliosis in response to a broad range of physiological stresses and insults (9). Although the molecular signature of reactive gliosis can vary considerably among injury paradigms, reactive astroglia show a set of common features, including cellular hypertrophy, up-regulation of intermediate filament proteins, and, in most cases, down-regulation of glutamine synthetase (GS). Although induction of reactive gliosis is ubiquitous after diverse types of retinal injuries, its function remains ambiguous. The discovery that preconditioning by a wide range of stressors also induces reactive gliosis has led to the suggestion that, at least in its early stages, reactive gliosis represents an coordinated response aimed at mitigating damage to nearby neurons (9). Severe and prolonged reactive gliosis, however, is usually associated with reduced neuronal viability, and it is unclear what regulates this transition between protective and destructive gliosis. It is ...

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Section: Discussionmentioning

confidence: 99%

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Melo

Miki

Rattner

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Although there has been no report on the effects of Olig2 on GPC proliferation, recent studies have shown that Olig2 can regulate the proliferation of multipotent NSCs (Ligon et al, 2007). In addition, Olig2 is critically involved in the proliferation of reactive astrocytes after injury (Chen et al, 2008). Thus, it is conceivable that the activation of Olig2 can promote the proliferative capacity of multiple cell types including GPCs.…”

Section: Discussion Olig2 Overexpression Increases Cellular Proliferamentioning

confidence: 99%

“…nated lesions in mature CNS (Arnett et al, 2004). More recent studies showed the involvement of Olig2 in the differentiation of neural and/or glial progenitors after injury (Buffo et al, 2005;Chen et al, 2008). It appears that Olig1 and Olig2 have distinct biological functions that could be separable from those of each other after injury and during development (Arnett et al, 2004;Buffo et al, 2005;Xin et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Differential and cooperative actions of Olig1 and Olig2 transcription factors on immature proliferating cells after contusive spinal cord injury

Kim

Hwang

Choi

et al. 2011

Glia

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“…Olig2 deletion in astrocytes reduces reactive astrocyte proliferation [95]. No data are currently available on injury-related signals involved in Olig2 induction in astrocytes.…”

Section: Intracellular Transduction Pathways and Cellular Reactivitymentioning

confidence: 99%

Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential

Buffo

Rolando

Ceruti

2010

Biochemical Pharmacology

287

260

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 Running title: Beneficial and detrimental outcomes of astrogliosis after central nervous system injury. Abbreviations:Ado, adenosine; AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate; AP1, activator protein1; AQP, acquaporin; BBB, blood-brain barrier; BDNF, brain-derived growth factor; bFGF, basic fibroblast growth factor; bHLH, basic helix loop helix; BMP, bone morphogenetic protein; CNS, central nervous system; CNTF, ciliary neurotrophic factor;COX-2, cyclooxigenase-2; CREB, cAMP response element binding; CSPGs, chondroitinsulphate proteoglycans; ERK, extracellular signal-regulated kinase; EGF, epidermal growth factor; Eph4A, ephrin 4A; Epo, erythropoietin; ET1, Endothelin 1; ET-R, endothelin receptor; GABA, gamma-aminobutyric acid; GDNF, glial cell-line derived neurotropic factor; GF, growth factor; GFAP, glial fibrillary acidic protein; GLAST, glutamate aspartate transporter; GLT1, glutamate transporter 1; GS, glutamine synthase; IFN , interferon-beta; IFNγ, interferon gamma; IGF1, insulin growth factor1; IL1β, interleukin 1 beta; IL2, interleukin 2; IL6, interleukin 6; IL10, interleukin 10; JAK, Janus protein tyrosine kinases; Lcn2, Lipocalin 2; MAPK, mitogen-activated protein kinase; MMP, matrix metalloprotease; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cell; NFkB, nuclear factor kappa B; NGF, nerve growth factor; NT3, neurotrophin 3; p38MAPK, p38 mitogen-activated protein kinase; PTEN, phosphatase and tensin homolog; SOCS, suppressor of cytokine signaling; SOD, superoxide dismutase; STAT, signal transducers and activators of transcription; TGFα, transforming growth factor alpha;TGFβ, transforming growth factor beta; TNFα, tumor necrosis factor alpha; VCAM1, vascular cell adhesion molecule-1; VEGF, vascular endothelial growth factor. Page 4 of 63A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 4...

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The Basic Helix-Loop-Helix Transcription Factor Olig2 Is Critical for Reactive Astrocyte Proliferation after Cortical Injury

Cited by 103 publications

References 28 publications

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2

Differential and cooperative actions of Olig1 and Olig2 transcription factors on immature proliferating cells after contusive spinal cord injury

Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential

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