title: Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated β-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(+/-)), 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. β-Catenin signaling is elevated in the developing Pten(+/-) cortex, and a heterozygous mutation in Ctnnb1 (encoding β-catenin), itself a candidate gene for ASD and microcephaly, can suppress Pten(+/-) cortical overgrowth. Thus, a balance of Pten and β-catenin signaling regulates normal brain growth trajectory by controlling cell number, and imbalance in this relationship can result in abnormal brain growth.
  
  
  CONCLUSIONS
  We report that Pten haploinsufficiency leads to a dynamic trajectory of brain overgrowth during development and altered scaling of neuronal and glial cell populations. β-catenin signaling is elevated in the developing cerebral cortex of Pten haploinsufficient mice, and a heterozygous mutation in β-catenin, itself a candidate gene for ASD and microcephaly, suppresses Pten(+/-) cortical overgrowth. This leads to the new insight that Pten and β-catenin signaling act in a common pathway to regulate normal brain growth trajectory by controlling cell number, and disruption of this pathway can result in abnormal brain growth.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Youjun
authors.identifier: http://orcid.org/0000-0003-4162-6897
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Julien
authors.initials: J
authors.lastname: Séjourné
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Clipperton-Allen
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida 33458 paged@scripps.edu.
authors.forename: Damon T
authors.initials: DT
authors.lastname: Page
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000002:abnormalities / Q000196:embryology / Q000254:growth & development; D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D057895:Haploinsufficiency / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051059:PTEN Phosphohydrolase; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D051176:beta Catenin; D000099260:Empty Spiracles Homeobox Proteins; C501070:RBBP8 protein, mouse; C546843:mTOR protein, mouse
keywords: Pten; autism; brain growth; cell types; macrocephaly; β-catenin