Retinal interneuron survival requires non-cell-autonomous Atrx activity

Abstract

ATRX is a chromatin remodeling protein that is mutated in several intellectual disability disorders including alpha-thalassemia/mental retardation, X-linked (ATR-X) syndrome. We previously reported the prevalence of ophthalmological defects in ATR-X syndrome patients, and accordingly we find morphological and functional visual abnormalities in a mouse model harboring a mutation occurring in ATR-X patients. The visual system abnormalities observed in these mice parallels the Atrx-null retinal phenotype characterized by interneuron defects and selective loss of amacrine and horizontal cells. The mechanisms that underlie selective neuronal vulnerability and neurodegeneration in the central nervous system upon Atrx mutation or deletion are unknown. To interrogate the cellular specificity of Atrx for its retinal neuroprotective functions, we employed a combination of temporal and lineage-restricted conditional ablation strategies to generate five different conditional knockout mouse models, and subsequently identified a non-cell-autonomous requirement for Atrx in bipolar cells for inhibitory interneuron survival in the retina. Atrx-deficient retinal bipolar cells exhibit functional, structural and molecular alterations consistent with impairments in neuronal activity and connectivity. Gene expression changes in the Atrx-null retina indicate defective synaptic structure and neuronal circuitry, suggest excitotoxic mechanisms of neurodegeneration, and demonstrate that common targets of ATRX in the forebrain and retina may contribute to similar neuropathological processes underlying cognitive impairment and visual dysfunction in ATR-X syndrome.

Recovery from impaired muscle growth arises from prolonged postnatal accretion of myonuclei in Atrx mutant mice

“…To further our understanding of the role of Atrx in tissue development, two mouse models have been generated; a conditional allele that results in protein ablation when bred to specific Cre driver lines and a hypomorphic mutation that mimics a human mutation in exon 2 producing reduced levels of an N-terminally truncated protein [ 15 , 16 ]. Although human patients are primarily hypomorphs, the Atrx-null model has shown similar, albeit slightly more severe, neuronal and retinal phenotypes than mice with the hypomorphic mutation [ 16 , 17 ], thereby validating the cKO mice as a good model to interrogate Atrx function. In this study, we utilized the conditional Atrx allele bred to a Myf5 -Cre driver line to generate muscle-specific Atrx cKO mice.…”

Neurodevelopmental Disorders Caused by Defective Chromatin Remodeling: Phenotypic Complexity Is Highlighted by a Review of ATRX Function

“…Other downregulated genes from this analysis include Gbx2, NeuroD4, Wif1, Nxph1, Nxph2, and Mbp, each of which could contribute to cognitive deficits observed in patients but require further analysis to asses their contribution to the phenotype (Levy et al, 2008(Levy et al, , 2014. In a similar experiment in the retina, 173 DEGs were identified with two-thirds upregulated (109 genes) and one-third (64 genes) downregulated (Lagali et al, 2016). Most of these genes were involved in the regulation of glutamate activity, ion channel regulation or encoded neuroprotective peptides, with four shown to be also dysregulated in the cortex (Csf2ra, Cbln4, Syt13, and Nlgn4).…”

“…The most widely used model is a floxed allele in which loxP sites flanked exon 18 which encodes the ATP-binding pocket ( Bérubé et al, 2005 ; Garrick et al, 2006 ). These animals have been crossed with several different tissue-specific Cre driver lines to inactivate ATRX in skeletal muscle progenitors ( Huh et al, 2012 ), Sertoli cells ( Bagheri-fam et al, 2011 ), osteobalsts ( Solomon et al, 2013 ), chondrocytres ( Solomon et al, 2009 ), the retina ( Medina et al, 2009 ; Lagali et al, 2016 ), and the developing forebrain ( Bérubé et al, 2005 ) among others. A second transgenic line ( Atrx Δ E 2 ) was developed by deleting exon 2 and replacing it with a SA-IRES-β-geo cassette ( Nogami et al, 2011 ; Shioda et al, 2011 ).…”

“…Inactivation of ATRX in retinal progenitors Atrx Pax 6 Cre resulted in a slight reduction in retina size and a specific reduction of interneurons, namely amacrine and horizontal cells ( Medina et al, 2009 ). Surprisingly, Atrx Pitf 1 aCre mice that ablates ATRX in a bi-potential progenitor that generates amacrine or horizontal cells did not recapitulate the phenotype, while inactivation with a bipolar cell specific Cre driver ( Atrx Vsx 2 Cre ) did not affect bipolar cell survival but did result in reduced amacrine and horizontal cells suggesting that interneuron survival was a cell non-autonomous effect ( Lagali et al, 2016 ). Additional characterization of these mice showed that the bipolar axons were mislocalized within the inner plexiform layer and many had axonal swellings or tortuous paths to their targets.…”

A new mouse model of ATR-X syndrome carrying a common patient mutation exhibits neurological and morphological defects

“…Deletion of ATRX in the whole central nervous system or in the forebrain (by Nestin-Cre and Foxg1-Cre , respectively) result in postnatal lethality within 48 hours of birth (Bérubé et al, 2005). Other models are viable into adulthood, with phenotypes revealing the importance of ATRX for the proper development and function of neurons (Tamming et al, 2017; Tamming et al, 2020), the retina (Lagali et al, 2016; Medina et al, 2009), chondrocytes (Solomon et al, 2009), skeletal muscle (Huh et al, 2012; Huh et al, 2017), and Sertoli cells (Bagheri-fam et al, 2011).…”