IDENTIFYING NOVEL GENETIC MODIFIERS OF BRAIN OVERGROWTH IN THE CORTEX OF A MOUSE MODEL OF MACROCEPHALY/AUTISM SYNDROME

Phosphatase and tensin homologue (PTEN) is a gene that, when mutated, can
cause macrocephaly/autism syndrome. The Pten mutant mouse model will help identify
genetic modifiers of Pten-related neurodevelopmental phenotypes, with the goal of
gaining insight into the polygenic nature of autism. We hypothesize that genes that
display spatiotemporal coexpression patterns similar to Pten in the developing brain are
candidates to genetically interact with Pten. Fbxw7, has been identified as a strong
candidate. We have conditionally deleted Fbxw7 (Fbxw7 cKO), Pten (Pten cHet), and
Pten and Fbxw7 together (Pten and Fbxw7 double mutant) in the developing cerebral
cortex. We found Fbxw7 cKO mice have decreased cortical mass and cell number,
increased cell density, hydrocephalus and premature lethality. Pten cHet mice display
increased cortical mass and cell number, with unchanged cell density and no
hydrocephalus or premature lethality. Strikingly, Pten and Fbxw7 double mutant mice
had the exact phenocopy of Pten cHet mice, indicating a surprising epistatic interaction
between Pten and Fbxw7, in which Pten overrides the effects of Fbxw7. Further work
will explore the mechanism of this interaction and will characterize cortical phenotypes
in mutant animals.