Brain-Region-Specific Contributions of FOXP1 to Autism and Intellectual Disability Phenotypes
| dc.contributor.advisor | Eisch, Amelia J. | en |
| dc.contributor.committeeMember | Konopka, Genevieve | en |
| dc.contributor.committeeMember | Powell, Craig M. | en |
| dc.contributor.committeeMember | Volk, Lenora J. | en |
| dc.contributor.committeeMember | Wu, Jiang I. | en |
| dc.creator | Araujo, Daniel John | en |
| dc.creator.orcid | 0000-0001-5781-2390 | |
| dc.date.accessioned | 2019-09-03T20:17:23Z | |
| dc.date.available | 2019-09-03T20:17:23Z | |
| dc.date.created | 2017-08 | |
| dc.date.issued | 2017-08-11 | |
| dc.date.submitted | August 2017 | |
| dc.date.updated | 2019-09-03T20:17:23Z | |
| dc.description.abstract | Mutations and deletions in the transcription factor FOXP1 are causative for severe forms of autism spectrum disorder (ASD) that are often comorbid with intellectual disability (ID). FOXP1 is enriched throughout the brain, with strong expression in the pyramidal neurons of the neocortex, the CA1/CA2 subfields of the hippocampus, and the medium spiny neurons of the striatum. Understanding the role that FOXP1 plays within these brain regions could allow for management of ASD and ID symptoms. This doctoral dissertation leverages multidisciplinary techniques and Foxp1 mutant mouse models to ascertain the role of Foxp1 in the brain and its contribution to specific ASD- and ID-relevant phenotypes. In the first chapter of this dissertation, I review the literature on the characteristics, demographics, and shared genetic underpinnings of ASD and ID and I review the work linking FOXP1 to these disorders. Afterwards, I describe the regional transcriptome regulated by Foxp1 within the brain and I correlate alterations in the gene expression profile of the striatum with deficits in communication (Chapter 2). Briefly, I utilized RNA-sequencing performed on Foxp1 heterozygous knockout animals to uncover the genes regulated by Foxp1 within the neocortex, hippocampus, and striatum. I also recorded the early postnatal ultrasonic vocalizations (USVs) of these animals and I was able to correlate changes in the properties of striatal medium spiny neurons with deficits in USV production. Next, I move onto using a Foxp1 conditional knockout (Foxp1cKO) mouse model to ascertain the contributions of Foxp1 in the neocortex and the hippocampus to ASD and ID-related behaviors (Chapter 3). In brief, I show that total loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/2 hippocampal subfields results in social communication deficits as well as hyperactivity and anxiety-like behaviors. I also show that Foxp1cKO mice display gross impairments in hippocampal-based spatial-learning tasks and I correlate these deficits with alterations in the expression of genes involved in hippocampal physiology and synaptic plasticity. In my final chapter (Chapter 4), I consider the implications that these data have on our understanding of the role that Foxp1 plays within the brain and I suggest research strategies to answer the new questions that my findings have generated. I also discuss the implications that this research has on our understanding of ASD and ID pathophysiology in general and I recommend future directions for work focused on managing these disorders. | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.oclc | 1117308708 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/7209 | |
| dc.language.iso | en | en |
| dc.subject | Forkhead Transcription Factors | en |
| dc.subject | Gene Expression | en |
| dc.subject | Neuronal Plasticity | en |
| dc.subject | Pyramidal Cells | en |
| dc.subject | Repressor Proteins | en |
| dc.subject | Spatial Learning | en |
| dc.subject | Synapses | en |
| dc.title | Brain-Region-Specific Contributions of FOXP1 to Autism and Intellectual Disability Phenotypes | en |
| dc.type | Thesis | en |
| dc.type.material | text | en |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Neuroscience | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |