The Chromatin-Remodeling Protein ATRX Is Critical for Neuronal Survival During Corticogenesis

J Clin Invest. 2005 Feb;115(2):258-67. doi: 10.1172/JCI22329.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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