DOI

10.17077/etd.6bzh-l0ei

Document Type

Dissertation

Date of Degree

Summer 2019

Access Restrictions

Access restricted until 09/04/2021

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Slusarski, Diane

First Committee Member

Weiner, Joshua

Second Committee Member

Phillips, Bryan

Third Committee Member

Kitamoto, Toshihiro

Fourth Committee Member

Baker, Sheila

Abstract

Neurodevelopmental disorders (ND) present a significant burden on society as over 5% of the US population is diagnosed with a ND. While environmental and biological factors have been associated with some cases of NDs, many still have unknown etiology. Strong comorbidities of NDs have been shown suggesting common biological processes of disease development. Sequencing technologies have allowed for the unprecedented identification of new candidate genes associated with NDs and many genes have been linked to multiple NDs. Developing robust methods to functionally validate these candidates is a critical next step for aiding patients with NDs. Using the zebrafish (Danio rerio), we characterized the developmental requirement of epilepsy candidate genes in the context of gene knockdown (KD). We demonstrated three different larval responses to pentylenetetrazol (PTZ) (hyperactive, hypoactive, or the same as control). We characterized the two genes resulting in a hyperactive response, Zinc Finger Homeobox 3 (ZFHX3) and Spectrin Repeat Domain Containing Nuclear Envelope Protein 1 (SYNE1), in greater detail. ZFHX3 is expressed in distinct brain regions during development and shows strong expression along nerve fiber tracts. SYNE1 shows broad expression during development that is enriched in the brain. Using CRISPR/Cas9 we generated a predicted null SYNE1 allele and recapitulated the seizure sensitivity phenotype in mutant larvae. Using a 60-hour behavioral assay we also demonstrate a generalized daytime hyperactivity in SYNE1 mutants. Our studies confirm ZFHX3 and SYNE1 as strong candidates for further study in epilepsy and suggest a role for SYNE1 in multiple NDs such as autism and attention-deficit/hyperactivity disorder.

Keywords

Behavior, Epilepsy, Genetics, Neurodevelopment

Pages

xiii, 170 pages

Bibliography

Includes bibliographical references (pages 116-130).

Copyright

Copyright © 2019 Tyson David Fuller

Available for download on Saturday, September 04, 2021

Included in

Genetics Commons

Share

COinS