Impact of PTEN mutations: Brain growth trajectory and scaling of cell types

  • Awarded: 2015
  • Award Type: Explorer
  • Award #: 360712

Abnormal patterns of head and brain growth have been reported in a subset of individuals with autism. A heterogeneous collection of genetic risk factors for autism and micro- and macrocephaly have been identified, including mutations in genes acting in the PI3K-AKT-mTOR (e.g., PTEN) and Wnt-beta-catenin (e.g., CTNNB1, CHD8 and TCF4) signaling pathways.

Damon Page and his colleagues at The Scripps Research Institute in La Jolla, California, are investigating whether the diverse risk factors associated with autism and abnormal brain growth converge on common biological pathways and cellular processes in the developing brain. The outcome of this work has relevance for stratifying individuals with autism into biologically and clinically meaningful subgroups.

Page’s team has previously shown that PTEN haploinsufficient mice have ASD-relevant brain overgrowth and social behavioral deficits1,2. Their recent pilot studies have found that brain overgrowth in PTEN haploinsufficient mice displays a dynamic pattern from birth to adulthood and coincides with excess neurons at birth and excess glia in adulthood.

They hypothesize that PTEN haploinsufficiency alters brain growth trajectory and scaling of neuronal and glial populations through elevated beta-catenin signaling. Testing this hypothesis will involve mapping beta-catenin activity in the developing PTEN haploinsufficient mouse brain and modulating beta-catenin activity in a PTEN haploinsufficient background. Primary readouts for the latter experiments will be measures of brain growth and social behavior.

Page and his colleagues predict that PTEN and Wnt-beta-catenin signaling act in a common pathway to control brain growth trajectory via cell number, and that this network may be a point of vulnerability in a subset of individuals with autism and abnormal brain growth.



1.Clipperton-Allen A.E. and D.T. Page Hum. Mol. Genet. 23, 3490-3505 (2014) PubMed
2.Page D.T. et alProc. Natl. Acad. Sci. USA 106, 1989-1994 (2009) PubMed
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