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

Kristopher R. Schwab

Abstract

Congenital heart disease (CHD) is the most common congenital anomaly worldwide, affecting approximately 1% of live births, corresponding to 1.35 million infants born with CHD each year, and remains a leading cause of infant mortality; therefore, it is urgent to understand the genetic and molecular mechanisms underlying CHD for advancing early diagnosis and treatment. Because many aspects of the Drosophila heart formation are highly reminiscent of vertebrate heart development, Drosophila melanogaster serves as a simple yet powerful model system for studying cardiac development and CHD. While at least eight Forkhead box (Fox) transcription factors (TFs) are required for proper cardiac development in mammals and mutations in four Fox genes have been linked to human congenital heart defects, relatively little is known about the molecular mechanisms or the downstream target genes by which these Fox TF-mediated cardiogenic functions are brought about. Our previous work showed that the Drosophila Fox genes jumeau (jumu) and Checkpoint suppressor 1-like (CHES-1-like) mediate three distinct categories of cardiac progenitor cell division—asymmetric, symmetric, and cell division at an earlier stage—by working in concert with the TF Myb to regulate the activity of Polo kinase. However, we also discovered that Fox TF motifs were significantly co-enriched with those of other known cardiogenic TFs in the enhancers of genes expressed in the heart, suggesting that jumu and CHES-1-like might be utilizing additional downstream target genes to regulate cardiac progenitor cell divisions. In chapter 2, I identified downstream targets of Jumu by comparing transcriptional expression profiles of flow cytometry-sorted mesodermal cells from wild-type embryos and embryos lacking jumu. Phenotypic analysis identified 21 jumu-regulated genes involved in cardiac progenitor cell division. Among these, Retinal Homeobox (Rx) was found to mediate all three known categories of cardiac progenitor cell divisions. Genetic interaction assays demonstrated synergistic cooperation between Rx and jumu in mediating asymmetric cardiac progenitor cell divisions. In chapter 3, I show that anilin homolog scraps (scra) is required for all three categories of cardiac progenitor cell divisions, although a threshold level of Scra is sufficient for asymmetric division. Genetic interaction assays uncovered synergistic relationships among scra, jumu, polo, and neb, but not between scra and CHES-1-like, indicating that scra operates within a jumu- and polo-regulated subnetwork mediating specific cardiac progenitor cell divisions. Cardiac mesoderm- and heart-specific knockdown experiments demonstrated that scra functions tissue-autonomously in cardiac progenitors to mediate symmetric divisions. In chapter 4, I report that the citron kinase sticky (sti), kinesin pavarotti (pav), and Rho GTPase tumbleweed (tum) are required for asymmetric, symmetric, and earlier cardiac progenitor cell divisions. Collectively, these findings illustrate how a single regulator can generate diverse developmental outcomes by selectively engaging distinct effector modules to regulate discrete cellular processes.

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