Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Biochemistry

Supervisor

Berube, Nathalie G.

Abstract

Chromatin architecture is an important regulator of gene expression, which dictates development. Mutations in one copy of the CTCF chromatin organizer gene cause intellectual disability and autism. Polymorphisms in CTCF have also been associated with increased risk for schizophrenia, a condition that overlaps in biological etiology with autism and intellectual disability. In this thesis, we sought to understand the role of CTCF in neurodevelopment using brain-specific conditional knockout and heterozygote mouse models. Using the Ctcf-null animals, we identify a cell-autonomous role for CTCF in regulating cortical interneuron development in the medial ganglionic eminence (MGE) through the transcriptional control of Lhx6. In the absence of CTCF, MGE-derived cortical interneuron subtypes are inappropriately specified such that their cortical laminar position is altered and there is a reduction in the number of cells expressing PV and SST. These features are rescued with viral-mediated re-expression of Lhx6. In addition, there is a concomitant increase in the expression of Lhx8, which specifies ventral telencephalic cell types in the MGE, indicating CTCF is an important regulator of cell fate choice in the MGE. To model the human condition associated with CTCF mutation, we generated mice heterozygous for Ctcf deletion in the developing brain (CtcfNestinHet). These mice had spontaneous hyperactivity and impaired spatial learning on behavioural testing. In addition to these behaviours, male mice had decreased sociability, altered aggression, and decreased anxiety. Together, this constellation of behaviours is reminiscent of other mouse models of schizophrenia, autism and intellectual disability. In addition, structural MRI revealed that CtcfNestinHet mouse brains had decreased white matter volume, suggestive of hypoconnectivity, a feature commonly attributed to the pathophysiology of autism. There were also significant volume decreases in the cerebellar nuclei, and an increase in the anterior cerebellar lobe. These findings provide further evidence for the emerging role of the cerebellum in cognition and in neurodevelopmental disorders. In summary, this work addresses the consequence of reduced CTCF expression in the developing brain at cellular, structural and behaviour levels, and thus significantly furthers our understanding of chromatin architecture regulation in neurodevelopmental disease.

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