Date of Award

2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

Abstract

Congenital heart disease (CHD) is the most common congenital anomaly affecting about 1.4 million children and adults in the United States, making it crucial to gain a deeper understanding of the genes and their genetic and molecular pathways that are involved in CHDs. With Drosophila melanogaster, commonly known as the fruit fly, exhibiting 70-80% conservation of genes with humans, the fruit fly is a powerful genetic model system to study these developmental processes involved in cardiogenesis. While at least eight Forkhead (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 was known about the molecular mechanisms or the downstream target genes by which these Fox TF-mediated cardiogenic functions are brought about. We showed previously that the Drosophila Fox genes jumeau ( jumu ) and Checkpoint suppressor homologue ( CHES-1-like ) initially specify cardiac progenitors by transcriptionally activating FGF and Wnt receptors and subsequently mediate three categories of cardiac progenitor cell division—asymmetric, symmetric, and cell division at an earlier stage. Additionally, jumu and CHES-1-like regulate Polo kinase activity to bring about these three types of cardiac progenitor cell division, while the two latter categories being regulated with the assistance of Myb. In chapter 2, I compared transcriptional expression profiles of wild-type and jumu loss-of-function embryos and identified twenty-one genes transcriptionally activated by jumu , but not by CHES-1-like . Phenotypic analysis of mutant alleles of these jumu -regulated genes show they are required in cardiac progenitor cell division. More specifically, I was able to investigate further that one of these genes, Retinal Homeobox (Rx) is required for all three types of cardiac progenitor cell division, asymmetric, symmetric, and cell division at an earlier stage. In chapters 3 and 4, I show the kinesin encoding gene, nebbish (neb) and the anilin encoding gene scraps (scra) are required for only two categories of jumu -regulated cardiac progenitor cell division: symmetric and cell division at an earlier stage. Synergistic genetic interactions between neb, jumu, Myb, and polo, as well as, between scra, jumu, polo, and neb were detected. Additionally, rescue of jumu mutations by ectopic cardiac mesoderm-specific expression of neb demonstrate further that neb is an integral component of a jumu -regulated subnetwork mediating cardiac progenitor cell divisions (Kump et al., 2021). My results thus illustrate how an individual regulator can utilize different combinations of downstream effectors to control distinct developmental processes.

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