Optic nerve crush induces spatial and temporal gene expression patterns in retina and optic nerve of BALB/cJ mice

Abstract

BackgroundCentral nervous system (CNS) trauma and neurodegenerative disorders trigger a cascade of cellular and molecular events resulting in neuronal apoptosis and regenerative failure. The pathogenic mechanisms and gene expression changes associated with these detrimental events can be effectively studied using a rodent optic nerve crush (ONC) model. The purpose of this study was to use a mouse ONC model to: (a) evaluate changes in retina and optic nerve (ON) gene expression, (b) identify neurodegenerative pathogenic pathways and (c) discover potential new therapeutic targets.ResultsOnly 54% of total neurons survived in the ganglion cell layer (GCL) 28 days post crush. Using Bayesian Estimation of Temporal Regulation (BETR) gene expression analysis, we identified significantly altered expression of 1,723 and 2,110 genes in the retina and ON, respectively. Meta-analysis of altered gene expression (≥1.5, ≤-1.5, p < 0.05) using Partek and DAVID demonstrated 28 up and 20 down-regulated retinal gene clusters and 57 up and 41 down-regulated optic nerve clusters. Regulated gene clusters included regenerative change, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. Expression of selected genes (Vsnl1, Syt1, Synpr and Nrn1) from retinal and ON neuronal clusters were quantitatively and qualitatively examined for their relation to axonal neurodegeneration by immunohistochemistry and qRT-PCR.ConclusionA number of detrimental gene expression changes occur that contribute to trauma-induced neurodegeneration after injury to ON axons. Nrn1 (synaptic plasticity gene), Synpr and Syt1 (synaptic vesicle fusion genes), and Vsnl1 (neuron differentiation associated gene) were a few of the potentially unique genes identified that were down-regulated spatially and temporally in our rodent ONC model. Bioinformatic meta-analysis identified significant tissue-specific and time-dependent gene clusters associated with regenerative changes, synaptic plasticity, axonogenesis, neuron projection, and neuron differentiation. These ONC induced neuronal loss and regenerative failure associated clusters can be extrapolated to changes occurring in other forms of CNS trauma or in clinical neurodegenerative pathological settings. In conclusion, this study identified potential therapeutic targets to address two key mechanisms of CNS trauma and neurodegeneration: neuronal loss and regenerative failure.

Translational profiling of retinal ganglion cell optic nerve regeneration in Xenopus laevis

“…5B). We also see that regenerating RGCs also undergo a robust endoplasmic reticulum stress response, along with an oxidative stress and inflammatory response, as previously reported in mouse (Sharma et al, 2014; Yasuda et al, 2014) and zebrafish models (McCurley and Callard, 2010; Veldman et al, 2007). By contrast, the groups of genes down-regulated following optic nerve crush are highly enriched for biological processes that are relevant in functional, connected RGCs, like synaptic communication factors.…”

“…7B, S8) and oxidative stress-response ( hmox1 ) systems (Fig. 7C) (Sharma et al, 2014; Veldman et al, 2007; Yasuda et al, 2014). Finally, we also see dramatic up-regulation in some, but not all, members of the Jak/Stat pathway, for example socs3 and IL-10 (Fig.…”

“…As during development, this active growth mode is associated with specific axonal growth associated genes and signaling pathways (Fischer and Leibinger, 2012). Based on developmental studies (Paranjpe et al, 2013; Peshkin et al, 2015; Shigeoka, 2016) and both mouse and zebrafish regenerative studies (Fischer and Leibinger, 2012; Sharma et al, 2014; Veldman et al, 2007; Yasuda et al, 2014), we predicted that we would find many of the same axonal growth associated genes and signaling. The kruppel-like family (klf) of transcription factors provides one example of a gene family that has been shown to be active during the period of axonal growth that occurs during normal development.…”

Early Gene Expression Profile in Retinal Ganglion Cell Layer After Optic Nerve Crush in Mice

“…Yasuda et al [42][43][44] further confirmed this evidence in whole retinas at 2 days after ONC by using RNA sequencing or cap analysis of gene expression technologies. Sharma et al 45 investigated temporal gene expression changes in retinas and optic nerves 3 to 28 days after ONC, and found that optic nerve Tnfrsf12a expression peaked at 3 days after ONC and decreased thereafter. This result is well correlated with the study of axotomized neuronal culture.…”

Dynamics of biomarkers in relation to aging and mortality

“…For AD, longitudinal changes in cerebrospinal fluid (CSF) and MRI biomarkers, such as CSF proteins (amyloid-β, amyloid precursor protein, tau protein, and other), magnetic resonance imaging brain volume and rate of atrophy, and in cognitive test scores, have been most often targeted. Several studies reported significant longitudinal changes in CSF biomarkers in AD patients, while others did not; some suggested that the shape of the association of AD biomarkers with disease severity can sometimes be nonlinear (e.g., sigmoidal or quadratic) and differ between biomarkers (Jack et al, 2013; Mattsson et al, 2012; Mouiha et al, 2012; Wildsmith et al, 2014). Other groups utilized longitudinal imaging measures to estimate temporal trajectories of cortical amyloid deposition before the onset of clinical symptoms to use them as potential predictors of progression to AD (Bilgel et al, 2015).…”