Under Pressure: Cellular and Molecular Responses During Glaucoma, a Common Neurodegeneration with Axonopathy

Nickells, Robert W.; Howell, Gareth R.; Soto, Ileana; John, Simon W. M.

doi:10.1146/annurev.neuro.051508.135728

Cited by 288 publications

(238 citation statements)

References 164 publications

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“…RGC death is involved in several retinal diseases such as glaucoma and optic ischemia, which often lead to vision loss and even blindness (59,60). Much effort has been undertaken to produce RGCs for cell-based therapies directly in vitro from various stem cells (61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

Kaczynski

Sethuramanujam

et al. 2015

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

103

111

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As with other retinal cell types, retinal ganglion cells (RGCs) arise from multipotent retinal progenitor cells (RPCs), and their formation is regulated by a hierarchical gene-regulatory network (GRN). Within this GRN, three transcription factors-atonal homolog 7 (Atoh7), POU domain, class 4, transcription factor 2 (Pou4f2), and insulin gene enhancer protein 1 (Isl1)-occupy key node positions at two different stages of RGC development. Atoh7 is upstream and is required for RPCs to gain competence for an RGC fate, whereas Pou4f2 and Isl1 are downstream and regulate RGC differentiation. However, the genetic and molecular basis for the specification of the RGC fate, a key step in RGC development, remains unclear. Here we report that ectopic expression of Pou4f2 and Isl1 in the Atoh7-null retina using a binary knockin-transgenic system is sufficient for the specification of the RGC fate. The RGCs thus formed are largely normal in gene expression, survive to postnatal stages, and are physiologically functional. Our results indicate that Pou4f2 and Isl1 compose a minimally sufficient regulatory core for the RGC fate. We further conclude that during development a core group of limited transcription factors, including Pou4f2 and Isl1, function downstream of Atoh7 to determine the RGC fate and initiate RGC differentiation.retinal development | neural development | transcription factors | cell fate specification | gene regulation A central question in neural development is how the extreme cellular diversity in the central nervous system arises from multipotent neural progenitors. The neural retina is an excellent system to address this question because of its well-defined structure and stereotypical cellular composition. The six neuronal cell types and one glial cell type (Müller glia) form a welllaminated tissue with the various types of cells positioned at distinct layers (1). Many of these cell types are composed of multiple subtypes with distinct functions (2). All cell types in the retina originate from a common pool of retinal progenitor cells (RPCs) following a distinct temporal order (3-5). The ordered births of the retinal cell types are caused by changes of competence in RPCs for the various retinal cell types (6). Both intrinsic and extrinsic mechanisms are involved in regulating the production of the various retinal cell types, but the intrinsic factors, mostly transcription factors, appear to play more deterministic roles in directing progenitor cells toward specific cell fates (5). Many such transcription factors have been identified by loss-and gain-of-function analyses, but these studies often fail to reveal the specific roles these factors play in the development of the cell types with which they are involved (7-9). RPCs are heterogeneous, as has been demonstrated by the nonuniform expression of many RPC genes (10-13). RPCs expressing specific genes, particularly those encoding transcription factors, although still multipotent, tend to be biased for certain retinal cell types. In a few cases, specific fac...

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Section: Discussionmentioning

confidence: 99%

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

Kaczynski

Sethuramanujam

et al. 2015

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

103

111

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“…To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models have been studied (reviewed in refs. 2,15,23). These studies identified changes in multiple genes/pathways related to immune responses, as well as structural and inflammatory changes in the ONH (8,24,25).…”

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confidence: 99%

“…glaucoma | astrocytes | complement | EGFR | WLDS G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1)(2)(3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4).…”

mentioning

confidence: 99%

“…Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5,8), but key questions remain unanswered (2,(13)(14)(15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve.…”

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confidence: 99%

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Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

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

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103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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“…2 The primary treatment goal is to reduce intraocular pressure (IOP), which is a risk factor for worsening of glaucoma-related neuropathy and axonal damage leading to vision loss. [3][4][5] Successful treatment for glaucoma is linked with good compliance/adherence, 6 yet many patients with glaucoma, especially those without symptoms, require multiple medications for adequate IOP control and this requirement may lead to compliance problems and consequently reduced efficacy.…”

mentioning

confidence: 99%

Early Clinical Experiences with Brinzolamide/Brimonidine Fixed Combination in Open-angle Glaucoma and Ocular Hypertension

Gandolfi¹

2017

European Ophthalmic Review

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T he fixed combination of brinzolamide 10 mg/ml and brimonidine 0.2% 2 mg/ml (BBFC; Simbrinza ® ) is an important addition to the glaucoma treatment choices currently available. Glaucoma is an increasingly prevalent disease worldwide, particularly in the elderly, and causes a serious burden of blindness. Fixed combinations of eye drops simplify treatment regimens, improving compliance, which helps maintain intraocular pressure (IOP) reductions. Registration of BBFC in Europe was supported by two phase III trials. In the first (n=560), after 6 months of treatment, BBFC twice daily lowered IOP by -1.4 mmHg more than brinzolamide alone, and by -1.5 mmHg more than brimonidine alone (least squares mean differences, p<0.0001 for both versus BBFC). BBFC was well tolerated with a safety profile similar to its two components. In the other of these trials (n=411), BBFC was non-inferior to brinzolamide and brimonidine given as separate doses concomitantly (B + B). The adverse events were similar in each group, with a slightly higher incidence in the B + B group. In the US, registration of BBFC in glaucoma was supported by three phase III and one phase IV trials, which also showed significantly greater IOP reduction with BBFC compared with its components alone and showed similar safety profiles. Additional phase IV studies are in progress to evaluate the combined use of BBFC with travoprost and timolol. BBFC has been clinically available in the US and Europe for only a short time, but its clinical trial efficacy suggests it will have a positive impact on real-world glaucoma and may have utility for earlier administration than its current third-or fourth-line use.

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Under Pressure: Cellular and Molecular Responses During Glaucoma, a Common Neurodegeneration with Axonopathy

Cited by 288 publications

References 164 publications

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Early Clinical Experiences with Brinzolamide/Brimonidine Fixed Combination in Open-angle Glaucoma and Ocular Hypertension

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