Date of Award

Spring 5-1-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Shaad M. Ahmad

Second Advisor

Rusty A. Gonser

Third Advisor

Kyu Hong Cho

Abstract

Cardiogenesis is a highly choreographed biological process requiring the precise integration of gene regulatory networks to govern cell division, fate determination, and spatial positioning. Disruptions in these mechanisms lead to congenital heart defects (CHDs), which affect approximately 1% of live births globally. Due to the evolutionary conservation of cardiac signaling pathways and the structural homologies between the Drosophila dorsal vessel and the early vertebrate heart tube, Drosophila melanogaster serves as a powerful model for dissecting the fundamental mechanisms of heart development. This dissertation investigates the molecular orchestration of cardiac development, specifically focusing on the roles of the transcription factors Jumu (a Forkhead box Transcription factor (Fox TF)) and Castor (a Zinc finger Transcription Factor) in regulating cardiac progenitor cell behavior. The research primarily establishes a diagnostic pipeline utilizing the Drosophila heart’s anatomical simplicity—consisting of a defined number of cardial and pericardial cells—to identify genes critical for progenitor cell proliferation. By analyzing null and hypomorphic mutants, this study categorizes cardiac cell division defects into three distinct types: symmetric division (expanding the Tinman-expressing pool), asymmetric division (generating Seven-up cardial/pericardial pairs), and early progenitor division (affecting the initial number of Svp progenitor cells). Using the well-established Drosophila dorsal vessel model, Chapter 3 further aims to bridge the Jumu-Polo Regulatory Gap. Previous studies identified a genetic hierarchy led by Jumu and CHES-1-like that activates the kinase Polo to mediate cell division. However, the lack of direct transcriptional regulation of polo by jumu suggested a missing link. This chapter identifies Backseat Driver as the intermediary, Jumu-regulated serine-threonine kinase that post-transcriptionally activates Polo, thereby completing the Forkhead box-mediated cardiogenic circuit. To maintain robustness and ensure proper cell division, redundant pathways are necessary. The Zinc finger transcription factor Castor — orthologous to mammalian CASZ1 — is essential for all three categories of cardiac progenitor division and for the fate specification of Seven-up cardial cells within the anterior aorta, providing a mechanistic basis for how CASZ1 mutations may contribute to vertebrate CHDs in Chapter 4. Finally, chapter 5 uncovers a dual role for Jumu in both cell division and the regulation of extracellular matrix (ECM) and basement membrane (BM) components, demonstrating that precise 3D cardiac morphogenesis requires the coordinated integration of biochemical signaling and structural organization. The chapter highlights how Jumu controls the expression of BM-encoding genes to maintain cardial cell positioning and, in turn, the structure of the heart. Collectively, these findings establish a comprehensive framework for understanding how Jumu and Castor coordinate the spatiotemporal requirements of heart formation, offering insights into the developmental origins of CHDs and highlighting conserved regulatory nodes as potential therapeutic targets.

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