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Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated Beta-Catenin Signaling
Objectives: Using Pten haploinsufficient mice, we address three related questions: 1) What is the trajectory of brain overgrowth? 2) Is the overgrowth caused by uniform scaling across cell types, or are some cell populations differentially impacted? 3) What is the genetic network in which Pten acts to influence brain growth? We hypothesized that Pten haploinsufficiency alters brain growth trajectory and scaling of neuronal and glial populations through elevated β-Catenin signaling.
Methods: We measured brain mass and applied the isotropic fractionator technique to estimate cell density and total cell number based on isolation of nuclei from brains of newborn and adult mice. To confirm findings using this approach, we applied immunohistochemical analyses. β-Catenin activity was assessed using a reporter mouse line.
Results: We found that Pten+/- brains were heavier than brains of wild type littermates at birth and in adulthood. Total cell number was elevated in the cerebral cortex of Pten+/- mice, without a corresponding change in cell density. The ratio of NeuN (neuronal marker) positive cells was significantly higher in Pten+/- than wild type cortex at birth, but lower than wild type in adulthood. Immunohistochemistry confirmed the presence of excess glia in the cortex of adult Pten+/- mice. Elevated β-Catenin signaling was observed in the cortex of newborn Pten+/- mice and haploinsufficiency for β-Catenin rescued cortex overgrowth in adulthood by suppressing the number of non-neuronal cells.
Conclusions: This work expands the characterization of Pten haploinsufficient mice. Our discovery that Pten haploinsufficiency leads to a non-uniform magnitude of brain overgrowth and scaling of neuronal and glial cell populations across developmental stages has implications for the identification of biomarkers and mechanisms of pathophysiology in ASD. In addition, our finding suggests that β-Catenin acts in a common network with Pten to regulate brain growth via control of cell number, and that this network may be a point of vulnerability and a target for therapeutic intervention for the subset of individuals with ASD and macrocephaly.