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

Abstract

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 ϩ/Ϫ ), 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 ϩ/Ϫ 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. ␤-Catenin signaling is elevated in the developing Pten ϩ/Ϫ cortex, and a heterozygous mutation in Ctnnb1 (encoding ␤-catenin), itself a candidate gene for ASD and microcephaly, can suppress Pten ϩ/Ϫ cortical overgrowth. Thus, a balance of Pten and ␤-catenin signaling regulates normal brain growth trajectory by controlling cell number, and imbalance in this relationship can result in abnormal brain growth.

Hyperconnectivity of prefrontal cortex to amygdala projections in a mouse model of macrocephaly/autism syndrome

“…We used a Cre driver that is expressed broadly in the cortex, rather than a Cre driver that is restricted to subcortical-projecting pyramidal cells, because we do not know at present if the effects of Pten +/− mutations on the development of this neuronal population are cell autonomous or non-cell autonomous. We have previously shown that Emx1-Cre + ; Pten loxp/+ mice recapitulate the cortical overgrowth phenotype seen in germ-line Pten +/− mice19. Testing social behaviour using three-chamber social approach test, we found that although adult female Emx1-Cre + ; Pten loxp/+ mice did not display a significant difference in allocation of chamber time as compared with controls, a within-group analysis revealed a lack of significant difference in time spent in the stimulus mouse versus object chambers (Fig.…”

“…Indeed, we have found that conditional homozygous mutation of Pten leads to massively increased p-S6 levels and decreased cell density throughout the newborn cerebral cortex, consistent with widespread hypertrophy, whereas we did not observe this phenotype upon conditional heterozygous mutation of Pten (ref. 19). We attribute this to an effect of Pten dosage: homozygous mutation of Pten shifts a wide variety of neural cell types towards a pathological state, with strong upregulation of mTORC1 activity and hypertrophy.…”

“…'s above normal), generally reduce PTEN protein levels1718, and cause macrocephaly/autism syndrome (OMIM #605309) in an autosomal dominant manner. A mouse model that approximates the germ-line heterozygous Pten ( Pten +/− ) mutations found in macrocephaly/autism syndrome displays a dynamic pattern of macroscale brain overgrowth due to altered proliferation and allocation of cell types, as well as selective impairments in ASD-relevant behaviours, particularly social behaviour19202122. The widespread macroscale brain overgrowth, together with selective behavioural impairments, suggests that cell types and circuits underlying social behaviour may be more vulnerable or less adaptable to desynchronized patterns of growth caused by Pten mutations20.…”

Wnt signaling networks in autism spectrum disorder and intellectual disability

“…Interestingly, PTEN has recently been identified to function with β-catenin to regulate normal brain growth, implicating PTEN in Wnt signaling. It was discovered that β-catenin signaling is elevated in a mouse model of Pten ( Pten +/-), and a heterozygous mutation in β-catenin suppresses the excessive cortical brain growth in Pten +/- mice [53]. This indicates that multiple ASD risk factors likely converge upon neural progenitor proliferation during embryonic brain development, potentially through regulation of canonical Wnt signaling.…”

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

“…However, there is also evidence that DISC1 is required for development of glutamatergic synapses [275,276], although it is not yet clear if this function is Wnt-dependent. The gene encoding PTEN, a cytoplasmic protein that suppresses Wnt/β-catenin signaling in the developing mouse cortex [277], has been repeatedly identified as a high-risk ASD susceptibility gene in human genomic studies [278,279,280,281]. Finally, single nucleotide variants of the Wnt/PCP pathway genes PRICKLE1 and PRICKLE2 were identified in whole exome sequencing of affected families [237,282].…”