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Publication Date

2020

First Advisor

Michael J.F. Barresi

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Biochemistry

Keywords

Autism spectrum disorders (ASD), Zebrafish, Neurodevelopment, Cortical lamination, In situ hybridization, Feedback regulation

Abstract

Neurodevelopment is characterized by a multitude of intricate, dynamic processes resulting in the establishment of a substantial, properly patterned population of neurons. Processes such as cell proliferation, migration, and differentiation must all successfully collaborate during development to form the brain, the tissue responsible for maintaining homeostasis, coordinating movement, and executive functioning. Therefore, neurodevelopmental diseases should be investigated in terms of these developmental mechanisms.

Autism Spectrum Disorders are a group of neurodevelopmental disorders characterized by broad alterations in brain morphology and a spectrum of atypical social behaviors. Everchanging diagnostic criteria, disease definitions, and heterogenous symptom type and expression over time renders ASD an incredibly difficult disorder to monitor and study. However, only in vivo studies modeling ASD based on associated genes and developmental pathways can uncover therapeutic potential.

Defects in Reelin signaling are implicated in the neurodevelopment of ASD in humans. We are studying the role of Reelin signaling during neurodevelopment in zebrafish to better understand the embryonic origins that may underlie ASD. Zebrafish provide unique advantages in disease modeling due to their transparency as embryos, rapid development, easy genetic manipulation, and large progeny. With zebrafish, we can analyze both embryonic neurodevelopment and later-stage adult behaviors.

Reelin signaling is best known to influence the patterns of neuronal migration during cortical development in mice. However, how the pathway members interact to mediate this influence and specifically how these events cause later adult-stage behavioral defects lacks clarity. Reelin acts through both the Very Low Density Lipoprotein receptor (Vldlr) and apolipoprotein E receptor 2 (ApoER2), and signals downstream through Disabled1 (Dab1). We have generated loss of function mutations via CRISPR/Cas9 mutagenesis in these key Reelin pathway members to define their individual and combinatorial roles during neuronal differentiation and positioning in the central nervous system. We find that these mutants display dynamic changes in Reelin pathway member expression patterns. In situ hybridization analyses across our mutants have revealed possible feedback mechanisms controlling these expression patterns.

Despite disruption due to COVID-19, we hypothesize that specific Reelin pathway interactions serve to support distinct early developmental events that have later behavioral consequences. Zebrafish mutants in the Reelin pathway provide a powerful system to better understand the links between embryonic development and adult behavioral manifestations. Future studies quantitating Reelin pathway transcript levels as well as analyzing cell-specific defects and social behavior will provide greater insight into the role of this pathway in the development of ASD.

Rights

2020 Grace Kathryn Nevil. Access limited to the Smith College community and other researchers while on campus. Smith College community members also may access from off-campus using a Smith College log-in. Other off-campus researchers may request a copy through Interlibrary Loan for personal use.

Language

English

Comments

69 pages : color illustrations. Includes bibliographical references (pages 66-69)

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