ATRX is required for maintenance of the neuroprogenitor cell pool in the embryonic mouse brain.
Mutations in the alpha-thalassemia mental retardation X-linked (ATRX) gene cause a spectrum of abnormalities including intellectual disability, developmental delay, seizures, and microcephaly. The ATRX protein is highly enriched at heterochromatic repetitive sequences adjacent to the centromere, and ATRX depletion results in chromosome congression, segregation, and cohesion defects. Here, we show that Cre-mediated inactivation of Atrx in the embryonic mouse (Mus musculus) brain results in expansion of cerebral cortical layer VI, and a concurrent thinning of layers II-IV. We observed increased cell cycle exit during early-mid neurogenesis, and a depletion of apical progenitors by late neurogenesis in the Atrx-null neocortex, explaining the disproportionate layering. Premature differentiation was associated with an increased generation of outer radial glia (oRG) and TBR2-expressing basal progenitors, as well as increased generation of early-born post-mitotic projection neurons. Atrx deletion also reduced the fidelity of mitotic spindle orientation in apical progenitors, where mutant cells were often oriented at non-parallel angles of division relative to the ventricular surface. We conclude that ATRX is required for correct lamination of the mouse neocortex by regulating the timing of neuroprogenitor cell differentiation.
Departments of Paediatrics and Biochemistry, Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, 800 Commissioners Road East, London, ON N6C 2V5, Canada.
Kieran
K
Ritchie
Departments of Paediatrics and Biochemistry, Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, 800 Commissioners Road East, London, ON N6C 2V5, Canada.
L Ashley
LA
Watson
Departments of Paediatrics and Biochemistry, Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, 800 Commissioners Road East, London, ON N6C 2V5, Canada.
Benjamin
B
Davidson
Departments of Paediatrics and Biochemistry, Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, 800 Commissioners Road East, London, ON N6C 2V5, Canada.
Yan
Y
Jiang
Departments of Paediatrics and Biochemistry, Children's Health Research Institute, University of Western Ontario, Victoria Research Laboratories, 800 Commissioners Road East, London, ON N6C 2V5, Canada nberube@uwo.ca.
Nathalie G
NG
Bérubé
ATRX; Cell division; Chromatin; Cortical lamination; Neurodevelopment