Date of Award

2017

Document Type

Dissertation/Thesis

Submission Date

October 2026

Thesis/Dissertation Advisor [Chair]

Macleod, Gregory

Abstract

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.

Comments

Includes bibliography.

Extent

21 p.

Identifier

FA00012611

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