Inactivation of the Akt Survival Pathway during Photoreceptor Apoptosis in the Retinal Degeneration Mouse

Jomary, Catherine; Cullen, Jason K.; Jones, Stephen E.

doi:10.1167/iovs.05-1176

Cited by 42 publications

(39 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Akt, another kinase implicated in retinal degeneration and cell survival (Johnson et al, 2005;Jomary et al, 2006) was slightly activated in degenerating VPP retinas as evidenced by the small increase in phosphorylation observed by Western blotting (Fig. 4).…”

Section: Lack Of Lif Prevents Activation Of Muller Glia Cells and Blomentioning

confidence: 92%

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Joly¹,

Lange²,

Thiersch³

et al. 2008

J. Neurosci.

119

168

View full text Add to dashboard Cite

Survival and death of photoreceptors in degenerative diseases of the retina is controlled by a multitude of genes and endogenous factors. Some genes may be involved in the degenerative process itself whereas others may be part of an endogenous defense system. We show in two models of retinal degeneration that photoreceptor death strongly induces expression of leukemia inhibitory factor (LIF) in a subset of Muller glia cells in the inner nuclear layer of the retina. LIF expression is essential to induce an extensive intraretinal signaling system which includes Muller cells and photoreceptors and is characterized by an upregulation of Edn2, STAT3, FGF2 and GFAP. In the absence of LIF, Muller cells remain quiescent, the signaling system is not activated and retinal degeneration is strongly accelerated. Intravitreal application of recombinant LIF induces the full molecular pathway including the activation of Muller cells in wild-type and Lif -/-mice. Interruption of the signaling cascade by an Edn2 receptor antagonist increases whereas activation of the receptor decreases photoreceptor cell death. Thus, LIF is essential and sufficient to activate an extensive molecular defense response to photoreceptor injury. Our data establish LIF as a Muller cell derived neuronal survival factor which controls an intrinsic protective mechanism that includes Edn2 signaling to support photoreceptor cell survival and to preserve vision in the injured retina.

show abstract

Section: Lack Of Lif Prevents Activation Of Muller Glia Cells and Blomentioning

confidence: 92%

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Joly¹,

Lange²,

Thiersch³

et al. 2008

J. Neurosci.

119

168

View full text Add to dashboard Cite

show abstract

“…However, the molecular mechanism by which light induces retinal degeneration is presently unclear. Apoptosis has been implicated as a common final pathway in retinal degeneration (16), and several apoptosisrelated genes have been shown to be activated during photoreceptor cell death. Casp1 and Casp2 were detected in the ONL of degenerating rat retina (17).…”

Section: Micrornas (Mirs)mentioning

confidence: 99%

Sponge Transgenic Mouse Model Reveals Important Roles for the MicroRNA-183 (miR-183)/96/182 Cluster in Postmitotic Photoreceptors of the Retina

Zhu

Sun

Okano

et al. 2011

Journal of Biological Chemistry

112

117

View full text Add to dashboard Cite

MicroRNA-183 (miR-183), miR-96, and miR-182 comprising the miR-183/96/182 cluster are highly expressed in photoreceptor cells. Although in vitro data have indicated an important role for this cluster in the retina, details of its in vivo biological activity are still unknown. To observe the impact of the miR-183/96/ 182 cluster on retinal maintenance and light adaptation, we generated a sponge transgenic mouse model that disrupted the activities of the three-component microRNAs simultaneously and selectively in the retina. Although our morphological and functional studies showed no differences between transgenic and wild type mice under normal laboratory lighting conditions, sponge transgenic mice displayed severe retinal degeneration after 30 min of exposure to 10,000 lux light. Histological studies showed that the outer nuclear layer thickness was dramatically reduced in the superior retina of transgenic mice. Real time PCR experiments in both the sponge transgenic mouse model and different microRNA stable cell lines identified Arrdc3, Neurod4, and caspase-2 (Casp2) as probable downstream targets of this cluster, a result also supported by luciferase assay and immunoblotting analyses. Further studies indicated that expression of both the cluster and Casp2 increased in response to light exposure. Importantly, Casp2 expression was enhanced in transgenic mice, and inhibition of Casp2 partially rescued their light-induced retinal degeneration. By connecting the microRNA and apoptotic pathways, these findings imply an important role for the miR-183/96/182 cluster in acute light-induced retinal degeneration of mice. This study demonstrates a clear involvement of miRs in the physiology of postmitotic cells in vivo. MicroRNAs (miRs)2 are endogenous and short (about 22 nucleotides) noncoding RNA molecules that bind to complementary sequences in the 3Ј-UTR of multiple target mRNAs, usually inhibiting their translation or causing their destabilization (1, 2). miRs are well conserved in eukaryotic organisms and widely expressed in different tissues and cell types (3). To date, 885 and 689 miRs have been identified in human and mouse genomes, respectively (miRBASE Release 13.0, March, 2009). Each miR regulates about 200 -800 target genes, and 60% of protein-encoding genes in humans are predicted to be regulated by miRs (4). Several miRs are tissue-specific, suggesting specialized roles in tissue differentiation and maintenance (5, 6). Progress toward identifying the in vivo functions of miRs has been limited, not only by the complex biology of these molecules but also by the experimental accessibility of the biological systems that they affect.The retina is a layered tissue in the back of the eye that contains specialized photoreceptor cells called rods and cones as well as other cell types, including ganglion, bipolar, horizontal, and amacrine cells (7). Its development, maintenance, and light-sensitive visual functions are highly regulated. At least 78 miRs are preferentially expressed in vertebrate retina (6,8,9), indic...

show abstract

“…PI3K-generated PI-3,4,5-P 3 accumulation is essential for apical membrane morphogenesis in Drosophila photoreceptor epithelial cells ( 251 ). During photoreceptor apoptosis in the retinal degeneration mouse model, PTEN, which counteracts the effects of PI3K by decreasing levels of 3 ′ -phosphorylated phosphoinositides, is activated and the downstream effectors of PI3K, Akt, and forkhead in rhabdomyosarcoma are inactivated ( 252 ). Interestingly, inactivation of PTEN in RPE cells results in retinal degeneration ( 253 ).…”

Section: Phosphoinositide Metabolism In the Retinamentioning

confidence: 99%

Phosphoinositide 3-kinase signaling in the vertebrate retina

Rajala

2010

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org was established by Streb et al. ( 3 ) in their classic paper that showed elevations in IP 3 caused intracellular release of bound calcium. Subsequently, 1,2-DG was found to stimulate protein kinase C (PKC), a serine/threonine kinase that phosphorylates a number of cellular proteins ( 4 ). Activation of the PLC/PKC cascade affects a variety of cellular events, including secretion, phagocytosis, smooth muscle contraction, proliferation, neurotransmission, and metabolism [see reviews by Rhee ( 5 ), Rhee and Choi ( 6 ), and Berridge ( 7 ) THE PI CYCLEIn the early 1950s, Hokin and Hokin ( 1, 2 ) discovered that addition of acetylcholine to brain slices stimulated the incorporation of phosphate and inositol but not glycerol into lipids; the major products of this incorporation were phosphatidylinositol (PI) and phosphatidic acid. Subsequent studies defi ned the reactions of the PI cycle and showed that the initial event was receptor-meditated activation of a phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PI-4,5-P 2 ) to 1,2-diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP 3 ). This increase in lipid synthesis reported by the Hokins was a recovery reaction that rapidly replenished PI separate from de novo PI synthesis. The role of 1,4, This work was supported by grants

show abstract

Inactivation of the Akt Survival Pathway during Photoreceptor Apoptosis in the Retinal Degeneration Mouse

Abstract: Taken in conjunction with previous studies, the data support a model in which photoreceptor cell death in the rd mouse is the result of combined inactivation of the Akt survival pathway and the activation of the two major apoptotic pathways.

Cited by 42 publications

References 54 publications

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Leukemia Inhibitory Factor Extends the Lifespan of Injured PhotoreceptorsIn Vivo

Sponge Transgenic Mouse Model Reveals Important Roles for the MicroRNA-183 (miR-183)/96/182 Cluster in Postmitotic Photoreceptors of the Retina

Phosphoinositide 3-kinase signaling in the vertebrate retina

Contact Info

Product

Resources

About