The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis

Bérubé, Nathalie G.; Mangelsdorf, Marie; Jagla, Magdalena; Vanderluit, Jackie; Garrick, David; Gibbons, Richard J.; Higgs, Douglas R.; Slack, Ruth S.; Picketts, David J.

doi:10.1172/jci200522329

Cited by 176 publications

(169 citation statements)

References 55 publications

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“…Atrx becomes highly expressed in the first differentiating cortical neurons at E13.5 ( Fig. 1 A, arrows), as we had previously described (Bérubé et al, 2005). At later stages (E16.5 and P0.5) it is widespread throughout the hippocampus, with staining in the CA1 and CA3 fields, the dentate gyrus and the subiculum, the transition zone between neocortex and hippocampus (Fig.…”

Section: Atrx Expression In the Developing Telencephalon And Hippocampussupporting

confidence: 75%

“…Foxg1Cre expression starting at E8.5 induces nearly complete recombination of the Atrx floxed allele in the forebrain (Bérubé et al, 2005). There is a significant reduction in the size of the hippocampus including the subiculum, in the Atrx Foxg1Cre mice.…”

Section: Targeted Inactivation Of Atrx Does Not Affect Proliferation mentioning

confidence: 97%

“…Fl/Fl mice have been described previously (Bérubé et al, 2005;Garrick et al, 2006 KiCre/ϩ mice. Subsequent matings of this progeny yielded mice that are p53-null in all tissues and Atrx/p53 dKO in the forebrain.…”

Section: Mouse Husbandry Genotyping and Tissue Preparation The Atrxmentioning

confidence: 99%

“…Subsequent matings of this progeny yielded mice that are p53-null in all tissues and Atrx/p53 dKO in the forebrain. Atrx and Cre genotyping was performed by PCR as previously described (Bérubé et al, 2005). Yolk sac or tail DNA was used for p53 genotyping.…”

Section: Mouse Husbandry Genotyping and Tissue Preparation The Atrxmentioning

confidence: 99%

“…Decreased ATRX activity gives rise to severe learning disabilities, indicating a vital role for the development of brain regions involved in learning and memory processing. We previously reported that mice with ATRX deficiency in the forebrain are born with a hypocellular cerebral cortex and hippocampus and fail to form a normal dentate gyrus (Bérubé et al, 2005). More recently, we identified ATRX as an important regulator of mitosis and found evidence of chromosome mis-segregation in ATRX-null mitotic neuroprogenitors in the developing telencephalon (Bérubé et al, 2000;Ritchie et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Neuronal Death Resulting from Targeted Disruption of the Snf2 Protein ATRX Is Mediated by p53

Seah¹,

Levy²,

Jiang³

et al. 2008

J. Neurosci.

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ATRX, a chromatin remodeling protein of the Snf2 family, participates in diverse cellular functions including regulation of gene expression and chromosome alignment during mitosis and meiosis. Mutations in the human gene cause alpha thalassemia mental retardation, X-linked (ATR-X) syndrome, a rare disorder characterized by severe cognitive deficits, microcephaly and epileptic seizures. Conditional inactivation of the Atrx gene in the mouse forebrain leads to neonatal lethality and defective neurogenesis manifested by increased cell death and reduced cellularity in the developing neocortex and hippocampus. Here, we show that Atrx-null forebrains do not generate dentate granule cells due to a reduction in precursor cell number and abnormal migration of differentiating granule cells. In addition, fewer GABA-producing interneurons are generated that migrate from the ventral telencephalon to the cortex and hippocampus. Staining for cleaved caspase 3 demonstrated increased apoptosis in both the hippocampal hem and basal telencephalon concurrent with p53 pathway activation. Elimination of the tumor suppressor protein p53 in double knock-out mice rescued cell death in the embryonic telencephalon but only partially ameliorated the Atrx-null phenotypes at birth. Together, these findings show that ATRX deficiency leads to p53-dependent neuronal apoptosis which is responsible for some but not all of the phenotypic consequences of ATRX deficiency in the forebrain.

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Section: Atrx Expression In the Developing Telencephalon And Hippocampussupporting

confidence: 75%

Section: Targeted Inactivation Of Atrx Does Not Affect Proliferation mentioning

confidence: 97%

Section: Mouse Husbandry Genotyping and Tissue Preparation The Atrxmentioning

confidence: 99%

Section: Mouse Husbandry Genotyping and Tissue Preparation The Atrxmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Neuronal Death Resulting from Targeted Disruption of the Snf2 Protein ATRX Is Mediated by p53

Seah¹,

Levy²,

Jiang³

et al. 2008

J. Neurosci.

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Role of ATRX Chromatin Remodelling Factor in α‐Thalassaemia X ‐Linked Mental Retardation

Young

Picketts

2016

Encyclopedia of Life Sciences

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α‐Thalassaemia X‐linked mental retardation (ATR‐X syndrome) is a congenital disorder typified by intellectual disability, abnormalities in growth and genital formation, and mild anaemia. Mutations resulting in the reduced function of the ATRX chromatin remodelling protein underlie these symptoms. Variability in the severity of disease characteristics may be associated either with mutations that affect different regions of ATRX or with individual variability in the chromosome landscape targeted by it. ATRX associates with proteins involved in regulating chromatin structure and repression of gene expression in repetitive, transcriptionally silent regions of the genome. Loss of ATRX function can be associated with altered gene expression, including reduced α‐globin expression; impairment in DNA repair; and the maintenance of chromosome stability, which may most critically affect normal development within tissues such as the brain and testes. The current standard of care for ATR‐X syndrome focuses on the management of symptoms, with targeted therapeutics lacking. Key Concepts ATR‐X syndrome is caused by loss‐of‐function mutations that result in the diminished expression, or reduced functionality, of the ATRX protein. Though clinical features of ATR‐X syndrome show variability, common characteristics include facial dysmorphism, stunted growth, hypotonia, microcephaly, intellectual disability, mild anaemia with detectable haemoglobin H (HbH) and genital abnormalities. ATR‐X syndrome is a nonprogressive disorder, involving abnormal development. ATRX is a widely expressed chromatin remodelling protein, whose function affects both genomic stability and gene expression. The histone chaperone complex formed by DAXX and ATRX is critical for loading the histone variant H3.3 onto chromatin. The function of ATRX may be most critical during the rapid expansion of cells that occurs during development within particular organs, such as the expansion of cortical neurons in the brain or Sertoli cells in the testes.

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Autism Spectrum Disorders

Anderson

2018

Developmental Neuropathology

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The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis

Cited by 176 publications

References 55 publications

Neuronal Death Resulting from Targeted Disruption of the Snf2 Protein ATRX Is Mediated by p53

Neuronal Death Resulting from Targeted Disruption of the Snf2 Protein ATRX Is Mediated by p53

Role of ATRX Chromatin Remodelling Factor in α‐Thalassaemia X ‐Linked Mental Retardation

Autism Spectrum Disorders

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