Dataset Information

Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.

ABSTRACT: S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4 ^(-/-) knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4 ^(-/-) mice revealed a robust increase in the expression of multiple photoreceptor- and Müller glia-specific genes, as well as the olfactory sensory neuron-specific gene, S100A5. This aberrant transcriptional profile is characterized by corresponding increases in the levels of proteins encoded by the aberrantly upregulated genes. Ingenuity pathway network and curated pathway analyses of differentially expressed genes in S100A4 ^(-/-) lenses identified Crx and Nrl transcription factors as the most significant upstream regulators, and revealed that many of the upregulated genes possess promoters containing a high-density of CpG islands bearing trimethylation marks at histone H3K27 and/or H3K4, respectively. In support of this finding, we further documented that S100A4 ^(-/-) knockout lenses have altered levels of trimethylated H3K27 and H3K4. Taken together, our findings suggest that S100A4 suppresses the expression of retinal genes during lens differentiation plausibly via a mechanism involving changes in histone methylation.

SUBMITTER: Maddala R

PROVIDER: S-EPMC7838418 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.

Maddala Rupalatha R Gao Junyuan J Mathias Richard T RT Lewis Tylor R TR Arshavsky Vadim Y VY Levine Adriana A Backer Jonathan M JM Bresnick Anne R AR Rao Ponugoti V PV

Scientific reports 20210126 1

S100A4, a member of the S100 family of multifunctional calcium-binding proteins, participates in several physiological and pathological processes. In this study, we demonstrate that S100A4 expression is robustly induced in differentiating fiber cells of the ocular lens and that S100A4 <sup>(-/-)</sup> knockout mice develop late-onset cortical cataracts. Transcriptome profiling of lenses from S100A4 <sup>(-/-)</sup> mice revealed a robust increase in the expression of multiple photoreceptor- and ...[more]

PMID: 33500475

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Project description:The primary energy substrate of the lens is glucose and uptake of glucose from the aqueous humor is dependent on glucose transporters. GLUT1, the facilitated glucose transporter encoded by Slc2a1 is expressed in the epithelium of bovine, human and rat lenses. In the current study, we examined the expression of GLUT1 in the mouse lens and determined its role in maintaining lens transparency by studying effects of postnatal deletion of Slc2a1. In situ hybridization and immunofluorescence labeling were used to determine the expression and subcellular distribution of GLUT1 in the lens. Slc2a1 was knocked out of the lens epithelium by crossing transgenic mice expressing Cre recombinase under control of the GFAP promoter with Slc2a1loxP/loxP mice to generate Slc2a1loxP/loxP;GFAP-Cre+/0 (LensΔGlut1) mice. LensΔGlut1 mice developed visible lens opacities by around 3 months of age, which corresponded temporally with the total loss of detectable GLUT1 expression in the lens. Spectral domain optical coherence tomography (SD-OCT) imaging was used to monitor the formation of cataracts over time. SD-OCT imaging revealed that small nuclear cataracts were first apparent in the lenses of LensΔGlut1 mice beginning at about 2.7 months of age. Longitudinal SD-OCT imaging of LensΔGlut1 mice revealed disruption of mature secondary fiber cells after 3 months of age. Histological sections of eyes from LensΔGlut1 mice confirmed the disruption of the secondary fiber cells. The structural changes were most pronounced in fiber cells that had lost their organelles. In contrast, the histology of the lens epithelium in these mice appeared normal. Lactate and ATP were measured in lenses from LensΔGlut1 and control mice at 2 and 3 months of age. At 2 months of age, when GLUT1 was still detectable in the lens epithelium, albeit at low levels, the amount of lactate and ATP were not significantly different from controls. However, in lenses isolated from 3-month-old LensΔGlut1 mice, when GLUT1 was no longer detectable, levels of lactate and ATP were 50% lower than controls. Our findings demonstrate that in vivo, the transparency of mature lens fiber cells was dependent on glycolysis for ATP and the loss of GLUT1 transporters led to cataract formation. In contrast, lens epithelium and cortical fiber cells have mitochondria and could utilize other substrates to support their anabolic and catabolic needs.

Project description:Recent studies have provided novel insights of co-development of the neural and vascular elements of the retina. Knowledge of these relationships are crucial to understand the impact of therapeutic measures in Retinopathy of Prematurity (ROP). ROP is imposed by therapeutic oxygen upon immature retinal blood vessels and neural cells causing delayed development and vascular regression. However, the impact of hyperoxia on developing retinal neurons is less understood because some aspects of normal development remain unknown. The metabolic changes during differentiation of retinal progenitor cells to functional neurons is one such aspect. We correlated immunomarkers of hypoxia with markers of metabolic change in developing retinal neurons during the early postnatal period in mice. The same marker proteins were studied in secondary lens fiber differentiation at postnatal day-3 (P3). Nuclear localization of the oxygen-sensitive subunits of hypoxia inducible factor, HIF-1α and HIF-2α was correlated with increasing mitochondrial content in differentiating neurons. Nuclear HIF was also correlated with AMP-dependent protein kinase (AMPK), and the AMPK phosphorylation target PPAR-gamma coactivator-1alpha (PGC-1α), the principal regulator of mitochondrial biogenesis. Expression of AMPK, PGC1α and HIF-2α in secondary fiber differentiation was visible in each profile of the lens equator. Strong nuclear localization for all markers was present at the onset of secondary fiber differentiation, and reflected changes in size, mitochondrial content, and metabolism. We speculate that the 'physiological hypoxia' that drives retinal vascular development is cell-specific and reliant upon neuronal differentiation and mitochondrial biogenesis. We suggest that the onset of differentiation increases energy consumption that is detected by AMPK. In turn AMPK increases mitochondrial biogenesis via PGC-1α. Mitochondrial oxygen consumption may then create intracellular hypoxia that activates HIF. This progression is congruent with the expression of these markers in secondary lens fiber differentiation and nuclear localization of HIF-2α. Nuclear localization of HIF-1α and HIF-2α in the postnatal retina is less defined than in the lens as it may involve the remnant of HIF expression from the embryonic period that is sustained and increased by intracellular hypoxia caused by increasing mitochondrial oxygen consumption. This the first report of the involvement of HIF-2α, AMPK and PGC-1α in lens development.

Dataset Information

Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.

Publications

Absence of S100A4 in the mouse lens induces an aberrant retina-specific differentiation program and cataract.

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