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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 2 Pg. 258-67 (Feb 2005) ISSN: 0021-9738 [Print] United States
• PMID: 15668733 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• Nuclear Proteins
• DNA Helicases
• Atrx protein, mouse
• X-linked Nuclear Protein

Topics

• Animals
• Animals, Newborn
• Apoptosis (genetics, physiology)
• Cell Differentiation (genetics, physiology)
• Cell Proliferation
• Chromatin (genetics, metabolism, pathology)
• DNA Helicases (genetics, metabolism)
• Gene Targeting
• Hippocampus (embryology, pathology)
• Mental Retardation, X-Linked (genetics, pathology)
• Mice
• Mice, Knockout
• Neocortex (embryology, pathology)
• Neurons (pathology, physiology)
• Nuclear Proteins (genetics, metabolism)
• Organogenesis (genetics, physiology)
• Stem Cells (pathology, physiology)
• X-linked Nuclear Protein