“Super p53” Mice Display Retinal Astroglial Changes

Juan J Salazar,Ana I Ramírez,Maria D Pinazo-Durán,Blanca Rojas,Roberto Gallego-Pinazo,José M Ramírez,Rosa De Hoz,Manuel Serrano,Steven Barnes

doi:10.1371/journal.pone.0065446

Abstract

Tumour-suppressor genes, such as the p53 gene, produce proteins that inhibit cell division under adverse conditions, as in the case of DNA damage, radiation, hypoxia, or oxidative stress (OS). The p53 gene can arrest proliferation and trigger death by apoptosis subsequent to several factors. In astrocytes, p53 promotes cell-cycle arrest and is involved in oxidative stress-mediated astrocyte cell death. Increasingly, astrocytic p53 is proving fundamental in orchestrating neurodegenerative disease pathogenesis. In terms of ocular disease, p53 may play a role in hypoxia due to ischaemia and may be involved in the retinal response to oxidative stress (OS). We studied the influence of the p53 gene in the structural and quantitative characteristics of astrocytes in the retina. Adult mice of the C57BL/6 strain (12 months old) were distributed into two groups: 1) mice with two extra copies of p53 (“super p53”; n = 6) and 2) wild-type p53 age-matched control, as the control group (WT; n = 6). Retinas from each group were immunohistochemically processed to locate the glial fibrillary acidic protein (GFAP). GFAP+ astrocytes were manually counted and the mean area occupied for one astrocyte was quantified. Retinal-astrocyte distribution followed established patterns; however, morphological changes were seen through the retinas in relation to p53 availability. The mean GFAP+ area occupied by one astrocyte in “super p53” eyes was significantly higher (p<0.05; Student’s t-test) than in the WT. In addition, astroglial density was significantly higher in the “super p53” retinas than in the WT ones, both in the whole-retina (p<0,01 Student’s t-test) and in the intermediate and peripheral concentric areas of the retina (p<0.05 Student’s t-test). This fact might improve the resistance of the retinal cells against OS and its downstream signalling pathways.

Highlights

The p53 tumour-suppressor gene is expressed ubiquitously in all cell types as an inactive, latent transcription factor that becomes active only when the cells are subjected to a variety of cellular insults such as DNA damage, radiation, hypoxia, telomere erosion, nutrient deprivation, transcription inhibition, depletion of nucleotide pools, oncogene expression, heat shock, or oxidative stress (OS), among others [1,2,3,4,5,6]
An evolving concept in cell and molecular neuroscience is that glial cells are far more fundamental to disease progression than previously thought, possibly through a noncellautonomous mechanism that is heavily dependent on p53 activities [10]
P53 is involved in oxidative stress-mediated astrocyte death after stimulation by the intercellular messenger nitric oxide (NO) [16] and by direct, transcription-independent signalling to the mitochondria [17]

Summary

Introduction

The p53 tumour-suppressor gene is expressed ubiquitously in all cell types as an inactive, latent transcription factor that becomes active only when the cells are subjected to a variety of cellular insults such as DNA damage, radiation, hypoxia, telomere erosion, nutrient deprivation, transcription inhibition, depletion of nucleotide pools, oncogene expression, heat shock, or oxidative stress (OS), among others [1,2,3,4,5,6]. The activation of p53 triggers a complex transcriptional program that, depending on the cell type, environment, and other contributing factors, induces a number of different responses, ranging from the induction of cell-cycle arrest, programmed cell death, and senescence, to DNA repair, control of mitochondrial respiration, and angiogenesis inhibition [7,8,9]. P53 promotes cell-cycle arrest by repressing cmyc transcription and/or by activating the cyclin-dependent kinase inhibitor p21cip/Cdkn1a [11,12,13,14]. It has been reported that NMDA-mediated CNS excitotoxicity generates a hypertrophic astrocyte morphology associated with changes in p53 expression and nuclear active caspase-3 in the absence of cell death [15]. P53 is involved in oxidative stress-mediated astrocyte death after stimulation by the intercellular messenger nitric oxide (NO) [16] and by direct, transcription-independent signalling to the mitochondria [17]

Methods

Results

Conclusion