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

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 10

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Increased apoptosis but normal proliferation in ATRX-deficient primary c...
Increased apoptosis but normal proliferation in ATRX-deficient primary cortical cultures. (A–I) Primary cultures of cortical progenitor cells were established from E12.5 telencephalon of AtrxFoxg1Cre mice (B, D, F, and H), control Cre– littermates (A, C, E, G), or heterozygote (Het) Cre+ littermates (I), and were grown for 6 days in culture. (A and B) BrdU staining for 16 hours of control (A) and knockout (B) colonies demonstrates that the proliferative capacity of the cultured cells is not diminished in the absence of ATRX protein expression. (C and D) Control progenitors show a high level of ATRX protein (red) in differentiating MAP2-positive cells (green). AtrxFoxg1Cre progenitors that are ATRX deficient (lack of red staining in D) still express high levels of MAP2. (E and F) Corresponding ATRX staining of clones in G and H demonstrates the absence of ATRX protein in AtrxFoxg1Cre progenitors. (G and H) Merged images of TUNEL-positive cells (green) and DAPI staining (blue). Note the increased level of TUNEL staining in AtrxFoxg1Cre cell colonies after 6 days in culture. (I) Heterozygous Cre+ progenitor cell clone stained for ATRX protein (red) and TUNEL (green), clearly showing that ATRX-deficient areas of the clone display higher levels of apoptosis. Magnification, ×20 (A–I).