Date of Award

8-26-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Advisor(s)

Jessica MacDonald

Subject Categories

Biology | Cell and Developmental Biology | Developmental Biology | Life Sciences | Neuroscience and Neurobiology

Abstract

The mammalian neocortex develops from a thin layer of neuroepithelial cells into a robust mosaic of differentiated neurons organized into distinct layers and functional areas. This process requires a complex choreography of transcription factors and epigenetic regulators to be spatially and temporally activated in a precise manner. Disruptions in any aspect of this delicate process may lead to neurodevelopmental disorders like autism spectrum disorder, schizophrenia, or intellectual disability. One such transcriptional coregulator that is a crucial regulator of neocortical development is Cited2. Previous work demonstrated that forebrain-specific Cited2 loss-of-function causes a reduction in neocortical progenitor proliferation which leads to reduced thickness of neocortical superficial layers, reduced neocortical length, and a reduction of interhemispheric connectivity throughout the neocortex. This dissertation elucidates the molecular mechanism by which CITED2 functions in the developing neocortex. Further, I explore the effects Cited2 cKO has on early post-natal and young adult behaviors and reveal disruptions in neonatal ultrasonic vocalizations, increased rearing behavior, and increased sensitization to repeated acoustic startle. Additionally, I perform transcriptome analysis of purified intermediate progenitor cells (IPCs) from Cited2 cKO and WT neocortices to elucidate affected biological processes that underpin the disrupted neocortical development and behavior of Cited2 cKO mice. I uncover novel deficits in primary cilia function and potential premature neurogenesis. Further, we investigate the role CITED2 plays in neuronal fate decisions of Layer V projection neurons, exploring the relationship between Cited2 and a recently discovered microRNA posited to modulate Cited2 expression. Finally, I delve into maternal diet alteration and show folic acid supplementation rescues morphological phenotypes generated by Cited2 cKO. In summary, we identify the Cited2 forebrain-specific knockout as an excellent novel system to study mechanisms underpinning neurodevelopment and the etiology of neurodevelopmental disorders.

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Open Access

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