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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.

Original publication




Journal article


J Clin Invest

Publication Date





258 - 267


Animals, Animals, Newborn, Apoptosis, Cell Differentiation, Cell Proliferation, Chromatin, DNA Helicases, Gene Targeting, Hippocampus, Mental Retardation, X-Linked, Mice, Mice, Knockout, Neocortex, Neurons, Nuclear Proteins, Organogenesis, Stem Cells, X-linked Nuclear Protein