, 2010b). Axin overexpression in NPC nuclei increased the levels of proneural targets of β-catenin,

Ngn1 and NeuroD1, by 4.3 ± 0.3-fold and 0.7 ± 0.2-fold, respectively ( Figure 7D). Intriguingly, blocking the interaction between nuclear Axin and β-catenin by expressing the Axin point mutant (CIDm) that was unable to bind β-catenin in the nucleus ( Xing et al., 2003) inhibited neuronal differentiation and maintained the NPC pool ( Figures 7E and 7F), particularly IPs ( Figures S7F and S7G). To further confirm the importance of the interaction between Axin and β-catenin in the nucleus, we designed a small peptide CID based on the protein sequence of the INK1197 manufacturer β-catenin-interacting domain of Axin ( Xing et al., 2003) and tagged the peptide with an SV40 T-antigen NLS to enable specific targeting of the CID peptide into the nucleus. CID-NLS effectively blocked

the interaction between Axin and β-catenin ( Figure S7H) and significantly inhibited neuronal differentiation in Doxorubicin manufacturer the mouse neocortex ( Figures 7G and 7H). These observations collectively indicate that nuclear Axin promotes neuronal differentiation in a β-catenin-dependent manner. The fate decision of NPCs between amplification and differentiation controls the number of neurons produced during brain development and ultimately determines brain

size. However, it is unclear how the NPCs make this fundamental choice. Here, we show that the subcellular localization of a signaling scaffold protein, 4-Aminobutyrate aminotransferase Axin, defines the activation of specific signaling networks in NPCs, thereby determining the amplification or neuronal differentiation of NPCs during embryonic development (Figure 8). Cytoplasmic Axin in NPCs enhances IP generation, which ultimately leads to increased neuron production, whereas nuclear Axin in IPs promotes neuronal differentiation. Intriguingly, the Cdk5-dependent phosphorylation of Axin facilitates the nuclear accumulation of the protein, thereby functioning as a “brake” to prevent the overproduction of IPs and induce neuronal differentiation. The drastic increase in the size of the cerebral cortex in the human brain, which is thought to underpin our unique higher-cognitive functions, is associated with a disproportionate expansion of cortical neurons, especially the upper-layer neurons. The expansion of cortical surface may result from increased numbers of neuroepithelial (NE) cells and RGs (Rakic, 2009) or from an amplified IP pool (Pontious et al., 2008). NE/RG augmentation evidently controls the global enlargement of cortical surface (Chenn and Walsh, 2002 and Vaccarino et al., 1999).