Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated β-Catenin Signaling

Abnormal patterns of head and brain growth are a replicated finding in a subset of individuals with autism spectrum disorder (ASD). It is not known whether risk factors associated with ASD and abnormal brain growth (both overgrowth and undergrowth) converge on common biological pathways and cellular mechanisms in the developing brain. Heterozygous mutations in PTEN (PTEN+/-), which encodes a negative regulator of the PI3K-Akt-mTOR pathway, are a risk factor for ASD and macrocephaly. Here we use the developing cerebral cortex of Pten(+/-) mice to investigate the trajectory of brain overgrowth and underlying cellular mechanisms. We find that overgrowth is detectable from birth to adulthood, is driven by hyperplasia, and coincides with excess neurons at birth and excess glia in adulthood. beta-Catenin signaling is elevated in the developing Pten(+/-) cortex, and a heterozygous mutation in Ctnnb1 (encoding beta-catenin), itself a candidate gene for ASD and microcephaly, can suppress Pten(+/-) cortical overgrowth. Thus, a balance of Pten and beta-catenin signaling regulates normal brain growth trajectory by controlling cell number, and imbalance in this relationship can result in abnormal brain growth.