Quantitative Retinal Protein Analysis after Optic Nerve Transection Reveals a Neuroprotective Role for Hepatoma-Derived Growth Factor on Injured Retinal Ganglion Cells

Hollander, Adam C.; D'Onofrio, Philippe M; Magharious, Mark; Lysko, Meghan D.; Koeberle, Paulo D.

doi:10.1167/iovs.11-8350

Cited by 26 publications

(25 citation statements)

References 73 publications

(98 reference statements)

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“…Upon neuronal injury, even distant neuronal injury, that role switches to one where glia are induced to destroy and remove the RGCs. Indeed, delayed RGC death was achieved by pharmacological inhibition of p-ERK [9], [24]. Here we further demonstrate that PD98059 is inhibiting p-ERK activated in glia and Müller cells early after RGC injury, rather than p-ERK in RGCs (which is undetectable in injured RGCs), indicating a glia-to-neuron paracrine effect.…”

Section: Discussionmentioning

confidence: 53%

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Neuronal Injury External to the Retina Rapidly Activates Retinal Glia, Followed by Elevation of Markers for Cell Cycle Re-Entry and Death in Retinal Ganglion Cells

et al. 2014

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Retinal ganglion cells (RGCs) are neurons that relay visual signals from the retina to the brain. The RGC cell bodies reside in the retina and their fibers form the optic nerve. Full transection (axotomy) of the optic nerve is an extra-retinal injury model of RGC degeneration. Optic nerve transection permits time-kinetic studies of neurodegenerative mechanisms in neurons and resident glia of the retina, the early events of which are reported here. One day after injury, and before atrophy of RGC cell bodies was apparent, glia had increased levels of phospho-Akt, phospho-S6, and phospho-ERK1/2; however, these signals were not detected in injured RGCs. Three days after injury there were increased levels of phospho-Rb and cyclin A proteins detected in RGCs, whereas these signals were not detected in glia. DNA hyperploidy was also detected in RGCs, indicative of cell cycle re-entry by these post-mitotic neurons. These events culminated in RGC death, which is delayed by pharmacological inhibition of the MAPK/ERK pathway. Our data show that a remote injury to RGC axons rapidly conveys a signal that activates retinal glia, followed by RGC cell cycle re-entry, DNA hyperploidy, and neuronal death that is delayed by preventing glial MAPK/ERK activation. These results demonstrate that complex and variable neuro-glia interactions regulate healthy and injured states in the adult mammalian retina.

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Section: Discussionmentioning

confidence: 53%

“…Intravitreal injections of the MAPK/ERK inhibitor PD98059 or control vehicle were as described [9], 1 hour after axotomy. Animals were placed in a stereotaxic frame and anesthetized with isoflurane, delivered through a gas anesthetic mask.…”

Section: Methodsmentioning

confidence: 99%

Neuronal Injury External to the Retina Rapidly Activates Retinal Glia, Followed by Elevation of Markers for Cell Cycle Re-Entry and Death in Retinal Ganglion Cells

et al. 2014

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“…Therefore, the decreased expression of these genes may contribute to abnormal myelin gene expression in this brain region. Although these genes were not significantly altered in the STR, hepatoma-derived growth factor ( HDGF ) and EPH receptor ( Ephb1 ), which have neuroprotective functions [88], [89], showed decreased expression in the STR of HIV-1Tg rats. In contrast to the PFC and STR, we found up-regulation of growth factors and receptors, including insulin receptor and platelet-derived growth factor ( Pdgfb ).…”

Section: Discussionmentioning

confidence: 95%

Transcriptome Sequencing of Gene Expression in the Brain of the HIV-1 Transgenic Rat

Cao

Wang

et al. 2013

PLoS ONE

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The noninfectious HIV-1 transgenic (HIV-1Tg) rat was developed as a model of AIDs-related pathology and immune dysfunction by manipulation of a noninfectious HIV-1gag-pol virus with a deleted 3-kb SphI-MscI fragment containing the 3′ -region of gag and the 5′ region of pol into F344 rats. Our previous studies revealed significant behavioral differences between HIV-1Tg and F344 control rats in their performance in the Morris water maze and responses to psychostimulants. However, the molecular mechanisms underlying these behavioral differences remain largely unknown. The primary goal of this study was to identify differentially expressed genes and enriched pathways affected by the gag-pol-deleted HIV-1 genome. Using RNA deep sequencing, we sequenced RNA transcripts in the prefrontal cortex, hippocampus, and striatum of HIV-1Tg and F344 rats. A total of 72 RNA samples were analyzed (i.e., 12 animals per group × 2 strains × 3 brain regions). Following deep-sequencing analysis of 50-bp paired-end reads of RNA-Seq, we used Bowtie/Tophat/Cufflinks suites to align these reads into transcripts based on the Rn4 rat reference genome and to measure the relative abundance of each transcript. Statistical analyses on each brain region in the two strains revealed that immune response- and neurotransmission-related pathways were altered in the HIV-1Tg rats, with brain region differences. Other neuronal survival-related pathways, including those encoding myelin proteins, growth factors, and translation regulators, were altered in the HIV-1Tg rats in a brain region-dependent manner. This study is the first deep-sequencing analysis of RNA transcripts associated the HIV-1Tg rat. Considering the functions of the pathways and brain regions examined in this study, our findings of abnormal gene expression patterns in HIV-1Tg rats suggest mechanisms underlying the deficits in learning and memory and vulnerability to drug addiction and other psychiatric disorders observed in HIV-positive patients.

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“…Intraocular injection of 36 μM hepatoma derived growth factor (~28 kDa) after ocular nerve excision in rats increases the survival of retinal ganglion cells - in part via PI3K-Akt and MAP kinase signaling (Hollander et al, 2012). …”

Section: New Additions To the Tear Proteomementioning

confidence: 99%

Lacritin and the tear proteome as natural replacement therapy for dry eye

Karnati¹,

Laurie²,

Laurie³

2013

Experimental Eye Research

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Tear proteins are potential biomarkers, drug targets, and even biotherapeutics. As a biotherapeutic, a recombinant tear protein might physiologically rescue the ocular surface when a deficiency is detected. Such a strategy pays more attention to the natural prosecretory and protective properties of the tear film and seeks to alleviate symptoms by addressing cause, rather than the current palliative, non-specific and temporary approaches. Only a handful of tear proteins appear to be selectively downregulated in dry eye, the most common eye disease. Lacritin and lipocalin-1 are two tear proteins selectively deficient in dry eye. Both proteins influence ocular surface health. Lacritin is a prosecretory mitogen that promotes basal tearing when applied topically. Levels of active monomeric lacritin are negatively regulated by tear tissue transglutaminase, whose expression is elevated in dry eye with ocular surface inflammation. Lipocalin-1 is the master lipid sponge of the ocular surface, without which residual lipids could interfere with epithelial wetting. It also is a carrier for vitamins and steroid hormones, and is a key endonuclease. Accumulation of DNA in tears is thought to be proinflammatory. Functions of these and other tear proteins may be influenced by protein-protein interactions. Here we discuss new advances in lacritin biology and provide an overview on lipocalin-1, and newly identified members of the tear proteome.

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Quantitative Retinal Protein Analysis after Optic Nerve Transection Reveals a Neuroprotective Role for Hepatoma-Derived Growth Factor on Injured Retinal Ganglion Cells

Abstract: We have identified numerous proteins that are differentially regulated at key time points after axotomy, and how the temporal profiles of their expression parallel RGC death. Using these data, we showed that HDGF is a potent neuroprotective factor for injured adult RGCs.

Cited by 26 publications

References 73 publications

Neuronal Injury External to the Retina Rapidly Activates Retinal Glia, Followed by Elevation of Markers for Cell Cycle Re-Entry and Death in Retinal Ganglion Cells

Neuronal Injury External to the Retina Rapidly Activates Retinal Glia, Followed by Elevation of Markers for Cell Cycle Re-Entry and Death in Retinal Ganglion Cells

Transcriptome Sequencing of Gene Expression in the Brain of the HIV-1 Transgenic Rat

Lacritin and the tear proteome as natural replacement therapy for dry eye

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