Cell-Autonomous β-Catenin Signaling Regulates Cortical Precursor Proliferation

Abstract

Overexpression of ␤-catenin, a protein that functions in both cell adhesion and signaling, causes expansion of the cerebral cortical precursor population and cortical surface area enlargement. Here, we find that focal elimination of ␤-catenin from cortical neural precursors in vivo causes premature neuronal differentiation. Precursors within the cerebral cortical ventricular zone exhibit robust ␤-catenin-mediated transcriptional activation, which is downregulated as cells exit the ventricular zone. Targeted inhibition of ␤-catenin signaling during embryonic development causes cortical precursor cells to prematurely exit the cell cycle, differentiate into neurons, and migrate to the cortical plate. These results show that ␤-catenin-mediated transcriptional activation functions in the decision of cortical ventricular zone precursors to proliferate or differentiate during development, and suggest that the cell-autonomous signaling activity of ␤-catenin can control the production of cortical neurons and thus regulate cerebral cortical size.

Cell-Autonomous Roles of ARX in Cell Proliferation and Neuronal Migration during Corticogenesis

“…This suggests that the level of ARX expression is important for the control of production of cortical neurons and the regulation of cerebral cortical size, similar to what has been described for ␤-catenin (Chenn and Walsh, 2003;Woodhead et al, 2006). Mutations in several genes are responsible for microcephaly in humans, including ASPM (abnormal spindle in microcephaly), microcephalin, CDK5RAP2, and CenPJ (Woods, 2004).…”

Cdk6-Dependent Regulation of G1 Length Controls Adult Neurogenesis

“…Hence, we injected mice with a single dose of BrdU, 24 hours before sacrifice. The cell cycle exit index was then scored by defining the ratio between BrdU þ /Ki-67 À cells and total BrdU þ cells in the DG, corresponding to the fraction of precursors leaving the cell cycle within 24 hours, as described previously [35][36][37][38] (Fig. 5A).…”

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

“…This effect results from increased VZ stem/precursor cell expansion by a reduction in cells exiting the cell cycle (Chenn and Walsh, 2002). Interestingly, targeted inhibition of ␤-catenin signaling results in the opposite effect, with stem cells prematurely exiting the cell cycle and differentiating into neurons (Woodhead et al, 2006).…”

“…Conversely, premature exit of the cell cycle by NSCs could result in a reduction in the area of the cortex, with a greater number of NSCs differentiating prematurely into neurons and thus reducing the NSC population below the level required to generate enough cells for normal brain development. This phenotype is seen in mice deficient in FGF2 (Vaccarino et al, 1999) or when ␤-catenin is inhibited in the NSC population (Woodhead et al, 2006). A similar phenotype could be caused by abnormalities of mitotic spindle orientation that would perturb the distribution of fate determinants and so alter cell fate (e.g., by premature neurogenesis) following division.…”