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Publication Date

2025-5

First Advisor

Michael J. F. Barresi

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Neuroscience

Keywords

zebrafish, embryonic development, bioelectric, calcium signaling, neural crest cell

Abstract

Timothy Syndrome (TS), an autosomal dominant disorder caused by a heterozygous de novo mutation in cacna1c, disrupts voltage-gated calcium (Ca²⁺) signaling through dysregulation of the Cav1.2 L-type Ca²⁺ channel. This dysregulation perturbs Ca²⁺-dependent bioelectric patterning, resulting in developmental anomalies, such as craniofacial malformations, including reductions of the mandible. The craniofacial structures are derived from cranial neural crest cells (CNCCs), a subset of the migratory, multipotent progenitor neural crest cell population, yet the mechanistic link between cacna1c-mediated Ca²⁺ disruption and CNCC behavior remains unresolved. Leveraging the zebrafish (Danio rerio) model, which offers well-defined CNCC-derived craniofacial structures and robust cellular analysis and imaging tools, we investigated cacna1c expression and function during embryogenesis. Hybridization chain reaction (HCR) revealed cacna1c expression in CNCC populations during segmentation. The knockdown of cacna1c using two splice-blocking morpholinos induced physiological defects, including somitic truncation and cardiac dysfunction. Genetic encoded voltage indicator (GEVI) Marina transgenic embryos demonstrated regional depolarization that is time sensitive, potentially demonstrating a physiological link to CNCC dysregulation. Immunofluorescence (IF) further identified perturbations in CNCC dynamics that primarily affected proliferation rates and migratory patterns. Together, these preliminary results showcase that Ca²⁺-dependent bioelectric signaling is disrupted in cacna1c knockdown, which alters CNCC dynamics. This work expands our understanding of how ion channel dysfunction, as seen in Timothy Syndrome, could influence NCC-driven processes and their broader developmental outcomes on morphogenesis.

Rights

©2025 Ruiyi Song. 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

72 pages: color illustrations. Includes bibliographical references (pages 58-63).

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