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The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis
Nathalie G. Bérubé, … , Ruth S. Slack, David J. Picketts
Nathalie G. Bérubé, … , Ruth S. Slack, David J. Picketts
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):258-267. https://doi.org/10.1172/JCI22329.
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Article Neuroscience

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

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Abstract

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal “birthdating” confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.

Authors

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

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Figure 1

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ATRX expression increases in postmitotic neurons. (A–E) Fixed tissue sec...
ATRX expression increases in postmitotic neurons. (A–E) Fixed tissue sections were treated with a polyclonal antibody (H300) detecting the full-length ATRX protein. (A) Coronal section through the cortical region at E13.5 reveals highest expression in the preplate (PP). (B) Sagittal section through the cortex at P0.5 shows high levels of ATRX staining in postmitotic neurons of the marginal zone (MZ), cortical plate (CP), and subplate (SP), but lower levels of staining in the proliferative subventricular (SVZ) and ventricular zones (VZ). (C) Sagittal section at P0.5 through the hippocampus demonstrates high ATRX levels in CA1, CA3, and dentate gyrus (DG) subregions. (D and E) Saggital section at P31 through the brain demonstrates that ATRX expression is maintained in the adult throughout the cortex (CX), the hippocampus (CA1 and CA3), and the dentate gyrus subregions. (F–K) Cortical progenitor cells dissected from E12.5 telencephalon were cultured for 6 days and were costained for ATRX (F) and for MAP2 (G), a marker of neuronal differentiation. The merged image (H) reveals coexpression of ATRX and MAP2 in the differentiated cells. In contrast, progenitors costained for ATRX (I) and proliferating cells as measured by BrdU incorporation (J) show low levels of ATRX in the BrdU-positive cells (K, merged image). Higher magnification (×20, K, bottom-right inset) image shows that BrdU and ATRX staining does not significantly overlap. Magnification, ×20 (A, C–K), ×10 (B).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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