Altered visual function and interneuron survival in Atrx knockout mice: Inference for the human syndrome
Regenerative Medicine, Ottawa Health Research Institute, Ottawa, Ontario, Canada K1H 8L6. Human Molecular Genetics
(Impact Factor: 6.39).
03/2009; 18(5):966-77. DOI: 10.1093/hmg/ddn424
ATRX is an SWI/SNF-like chromatin remodeling protein that is mutated in several X-linked mental retardation syndromes, including the ATR-X syndrome. In mice, Atrx expression is widespread and attempts to understand its function in brain development are hampered by the lethality associated with ubiquitous or forebrain-restricted ablation of this gene. One way to circumvent this problem is to study its function in a region of the brain that is dispensable for long-term survival of the organism. The retina is a well-characterized tractable model of CNS development and in our review of 202 ATR-X syndrome patients, we found ocular defects present in approximately 25% of the cases, suggesting that studying Atrx in this tissue will provide insight into function. We report that Atrx is expressed in the neuroprogenitor pool in embryonic retina and in all cell types of the mature retina with the exception of rod photoreceptors. Conditional inactivation of Atrx in the retina during embryogenesis ultimately results in a loss of only two types of neurons, amacrine and horizontal cells. We show that this defect does not arise from a failure to specify these cells but rather a defect in interneuron differentiation and survival post-natally. The timing of cell loss is concomitant with light-dependent changes in synaptic organization in the retina and with a change in Atrx subnuclear localization within these interneurons. Moreover, these interneuron defects are associated with functional deficits as demonstrated by reduced b-wave amplitudes upon electroretinogram analysis. These results implicate a role for Atrx in interneuron survival and differentiation.
Available from: Giuseppina Barsacchi
- "This study indicates that 39% of the selected genes are involved in either transcription or translation regulation. Indeed, Rx1 controls the expression of JHDM1d and Atrx, two chromatine remodelers involved in central nervous system development (Tsukada et al., 2010; Medina et al., 2009), several homeodomain and bHLH transcription factors, including Rx1 itself, an RNA polymerase II subunit, as well as proteins involved in translation (including ribosomal protein L9, mitochondrial ribosomal protein S5 and Eif4g) and in RNA binding (Gtpbp1, scaf4, and Rbm24). These data suggest a key hierarchical position for Rx1 in controlling gene expression at multiple levels in retinal progenitors. "
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The transcription factor Rx1, also known as Rax, controls key properties of retinal precursors including migration behavior, proliferation, and maintenance of multipotency. However, Rx1 effector genes are largely unknown.
To identify genes controlled by Rx1 in early retinal precursors, we compared the transcriptome of Xenopus embryos overexpressing Rx1 to that of embryos in which Rx1 was knocked-down. In particular, we selected 52 genes coherently regulated, i.e., actived in Rx1 gain of function and repressed in Rx1 loss of function experiments, or vice versa. RT-qPCR and in situ hybridization confirmed the trend of regulation predicted by microarray data for the selected genes. Most of the genes upregulated by Rx1 are coexpressed with this transcription factor, while downregulated genes are either not expressed or expressed at very low levels in the early developing retina. Putative direct Rx1 target genes, activated by GR-Rx1 in the absence of protein synthesis, include Ephrin B1 and Sh2d3c, an interactor of ephrinB1 receptor, which represent candidate novel effectors for the migration promoting activity of Rx1.
This study identifies previously undescribed Rx1 regulated genes mainly involved in transcription regulation, cell migration/adhesion, and cell proliferation that contribute to delineate the molecular mechanisms underlying Rx1 activities.
Developmental Dynamics 10/2014; 243(10). DOI:10.1002/dvdy.24145 · 2.38 Impact Factor
Available from: Emma C Goodall
- "Cell death could be partially rescued in the forebrain by removal of p53 suggesting that Atrx could be important for maintaining genomic stability . However, Atrx ablation in the retina and in bone is not associated with extensive apoptosis suggesting that the function of Atrx in cell survival may be more complex , . In this regard, several other studies have implied that stress signaling, cell-cell signaling or Daxx-mediated pathways are important survival mechanisms for Atrx-deficient cells , , , . "
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ABSTRACT: Prevalent cell death in forebrain- and Sertoli cell-specific Atrx knockout mice suggest that Atrx is important for cell survival. However, conditional ablation in other tissues is not associated with increased death indicating that diverse cell types respond differently to the loss of this chromatin remodeling protein. Here, primary macrophages isolated from Atrx(f/f) mice were infected with adenovirus expressing Cre recombinase or β-galactosidase, and assayed for cell survival under different experimental conditions. Macrophages survive without Atrx but undergo rapid apoptosis upon lipopolysaccharide (LPS) activation suggesting that chromatin reorganization in response to external stimuli is compromised. Using this system we next tested the effect of different apoptotic stimuli on cell survival. We observed that survival of Atrx-null cells were similar to wild type cells in response to serum withdrawal, anti-Fas antibody, C2 ceramide or dexamethasone treatment but were more sensitive to 5-fluorouracil (5-FU). Cell survival could be rescued by re-introducing Atrx or by removal of p53 demonstrating the cell autonomous nature of the effect and its p53-dependence. Finally, we demonstrate that multiple primary cell types (myoblasts, embryonic fibroblasts and neurospheres) were sensitive to 5-FU, cisplatin, and UV light treatment. Together, our results suggest that cells lacking Atrx are more sensitive to DNA damaging agents and that this may result in enhanced death during development when cells are at their proliferative peak. Moreover, it identifies potential treatment options for cancers associated with ATRX mutations, including glioblastoma and pancreatic neuroendocrine tumors.
PLoS ONE 12/2012; 7(12):e52167. DOI:10.1371/journal.pone.0052167 · 3.23 Impact Factor
Available from: link.springer.com
- "In the mouse retina, loss of Atrx leads to a selective reduction in amacrine and horizontal cell populations in the postnatal period . Various amacrine cell subtypes are affected, including glycinergic, cholinergic, and dopaminergic neurons . "
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ABSTRACT: Retinal neurons are highly vulnerable to a diverse array of neurotoxic stimuli that leads to their degeneration, which is a major contributor to blindness. This review summarizes the role of epigenetic factors in mediating neuronal homeostasis and survival to protect against cell death and neurodegenerative conditions. Studies in human patients and mouse models implicate numerous chromatin modifications in neuroprotective processes including histone protein acetylation and methylation, DNA methylation, and ATP-dependent nucleosome remodeling. Recent research has begun to uncover specific epigenetic mechanisms invoked by neurotoxic stimuli. Continued investigation in this area will be the key to the generation of therapeutic strategies for the intervention of retinal neurodegenerative diseases.
Journal of ocular biology, diseases, and informatics 09/2011; 4(3):111-20. DOI:10.1007/s12177-012-9080-3
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