The morphology and spatial arrangement of astrocytes in the optic nerve head of the mouse

Sun, Daniel; Lye-Barthel, Ming; Jakobs, Tatjana C.

doi:10.1002/cne.22110

Cited by 7 publications

(11 citation statements)

References 49 publications

(65 reference statements)

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“…3B) and the MTZ (Fig. 3C), axons were enwrapped by astrocytes with transverse orientation, as previously reported (10). Surprisingly, even in this strain, which does develop RGC loss with age (8), axons at the glial lamina ( Fig.…”

Section: Normal Onh Astrocytes Constitutively Internalize Evulsed Axonalsupporting

confidence: 84%

Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma

Nguyen

Soto

Kim

et al. 2011

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

193

179

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Optic nerve head (ONH) astrocytes have been proposed to play both protective and deleterious roles in glaucoma. We now show that, within the postlaminar ONH myelination transition zone (MTZ), there are astrocytes that normally express Mac-2 (also known as Lgals3 or galectin-3), a gene typically expressed only in phagocytic cells. Surprisingly, even in healthy mice, MTZ and other ONH astrocytes constitutive internalize large axonal evulsions that contain whole organelles. In mouse glaucoma models, MTZ astrocytes further upregulate Mac-2 expression. During glaucomatous degeneration, there are dystrophic processes in the retina and optic nerve, including the MTZ, which contain protease resistant γ-synuclein. The increased Mac-2 expression by MTZ astrocytes during glaucoma likely depends on this γ-synuclein, as mice lacking γ-synuclein fail to up-regulate Mac-2 at the MTZ after elevation of intraocular pressure. These results suggest the possibility that a newly discovered normal degradative pathway for axons might contribute to glaucomatous neurodegeneration.DBA/2J mice | retinal ganglion cell | Sncg G laucoma, a neurodegenerative disorder that kills retinal ganglion cells (RGCs), affects more than 60 million people and is the second leading cause of blindness worldwide (1). In glaucomatous retinas, both astrocytes and Müller glia increase their reactivity (2, 3). Within the orbital portion of the optic nerve, astrocytes increase in number and reactivity (4). Within the optic nerve head (ONH), astrocytes also increase reactivity in glaucoma animal models and in the human disease (5). These ONH astrocytes are of particular interest as they enwrap axons at the location where damage would account for the arcuate vision field loss characteristic of glaucoma.Here, we identify a spatially discrete population of astrocytes within the ONH, those at the myelination transition zone (MTZ), which express the phagocytosis-related gene Mac-2. Surprisingly, astrocytes throughout the ONH including the MTZ phagocytose large axonal evulsions even in unaffected mice. Mac-2 expression is increased in optic nerve astrocytes upon injury and at the MTZ in two mouse models of glaucoma. In glaucomatous mice, there are protease resistant forms of γ-synuclein, including at the MTZ. Further, mice lacking γ-synuclein fail to up-regulate Mac-2 at the MTZ in response to increased intraocular pressure (IOP). These results suggest the possibility that failure to properly clear axon-derived material at the MTZ, including γ-synuclein, may contribute to axon loss in glaucoma.

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Section: Normal Onh Astrocytes Constitutively Internalize Evulsed Axonalsupporting

confidence: 84%

Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma

Nguyen

Soto

Kim

et al. 2011

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

193

179

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“…In optic nerves of control CxWT mice, GFAP was expressed in thick processes of astrocytes that formed the glial tubes, which ensheathed bundles of SMI32-positive axons creating a characteristic honeycomb mosaic (ref. 35 and Figure 6A). We found significant changes in the structure of the optic nerve at 8 weeks after the initial microbead injection.…”

Section: Cx36mentioning

confidence: 90%

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Akopian¹,

Kumar²,

Ramakrishnan³

et al. 2017

Journal of Clinical Investigation

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The progressive death of retinal ganglion cells and resulting visual deficits are hallmarks of glaucoma, but the underlying mechanisms remain unclear. In many neurodegenerative diseases, cell death induced by primary insult is followed by a wave of secondary loss. Gap junctions (GJs), intercellular channels composed of subunit connexins, can play a major role in secondary cell death by forming conduits through which toxic molecules from dying cells pass to and injure coupled neighbors. Here we have shown that pharmacological blockade of GJs or genetic ablation of connexin 36 (Cx36) subunits, which are highly expressed by retinal neurons, markedly reduced loss of neurons and optic nerve axons in a mouse model of glaucoma. Further, functional parameters that are negatively affected in glaucoma, including the electroretinogram, visual evoked potential, visual spatial acuity, and contrast sensitivity, were maintained at control levels when Cx36 was ablated. Neuronal GJs may thus represent potential therapeutic targets to prevent the progressive neurodegeneration and visual impairment associated with glaucoma.

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“…Rodents are susceptible to the disease, yet mice do not show staining for any collagen other than collagen 4 associated with blood vessels, and the ONH of rats contains only sparse collagenous septa (Morrison et al 1995;May and LutjenDrecoll 2002;Sun et al 2009). A commonality between ONH of humans and all other species, including rodents, is that this region contains an abundance of astrocytes that line the pores of the lamina cribrosa and ensheath the axons, or, in rodents, form glial tubes around axon bundles that visually resemble a lamina cribrosa so much that they are referred to as the "glial lamina" (Morcos and Chan-Ling 2000;Howell et al 2007;Sun et al 2009). In addition to astrocytes, the human laminar region contains lamina cribrosa cells (Hernandez et al 1988).…”

Section: Gene Expression In the Onh In Glaucomamentioning

confidence: 99%

Differential Gene Expression in Glaucoma

Jakobs

2014

Cold Spring Harbor Perspectives in Medicine

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In glaucoma, regardless of its etiology, retinal ganglion cells degenerate and eventually die. Although age and elevated intraocular pressure (IOP) are the main risk factors, there are still many mysteries in the pathogenesis of glaucoma. The advent of genome-wide microarray expression screening together with the availability of animal models of the disease has allowed analysis of differential gene expression in all parts of the eye in glaucoma. This review will outline the findings of recent genome-wide expression studies and discuss their commonalities and differences. A common finding was the differential regulation of genes involved in inflammation and immunity, including the complement system and the cytokines transforming growth factor b (TGFb) and tumor necrosis factor a (TNFa). Other genes of interest have roles in the extracellular matrix, cell -matrix interactions and adhesion, the cell cycle, and the endothelin system.

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The morphology and spatial arrangement of astrocytes in the optic nerve head of the mouse

Cited by 7 publications

References 49 publications

Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma

Myelination transition zone astrocytes are constitutively phagocytic and have synuclein dependent reactivity in glaucoma

Targeting neuronal gap junctions in mouse retina offers neuroprotection in glaucoma

Differential Gene Expression in Glaucoma

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