Project Summary Myogenic defects, which includes congenital heart malformations as well as congenital muscular dystrophies are the most prevalent classes of birth defects in the human population, with an incident rate as high as 10 in 1000 live births. A significant number of these cases are termed sporadic, which are largely the result of interactions between a number of independent genetic loci and alleles. To aid in our understanding of the polygenic nature of congenital myogenic defects, it remains imperative to continue to identify new gene regulatory partners that may play a role in the process of embryonic heart and skeletal muscle patterning. Our laboratory has recently identified a cofactor, Akirin, that is responsible for interfacing transcription factor activity with chromatin remodeling machinery to facilitate gene expression during a variety of skeletal myogenic and cardiogenic processes. To date, the number of developmentally critical transcription factors known to interact with Akirin remains frustratingly low, despite the myriad developmental processes known to require Akirin for proper function. Excitingly, our preliminary data suggests that Akirin likely regulates insect embryonic heart development and/or skeletal muscle development through interactions with the GATA-family member Pannier, a zinc finger transcription factor identified as key for embryonic segmentation as well as cardiomyoblast specification. This project therefore involves simultaneous pursuit of two related specific aims: 1) Using a combination of genetic, biochemical, and live imaging techniques, will confirm the importance of Akirin/Pannier interactions during development, and 2) We will deploy a focused candidate screen for Akirin interacting loci, based on a small number (25) of predicted Akirin interactors. This work will provide key data for understanding the role of Akirin in the process of skeletal muscle and heart formation, and generate a further list of Akirin-interacting locian Akirin interactome- that will shed light on other myogenic regulatory nodes that require Akirin. Critically, in keeping with the goals of the Su RE award mechanism, this project will support the research activities of the Pl, whose previously NIH-supported laboratory has an established track record of recruiting talented undergraduate researchers from diverse backgrounds. Members of the Nowak Laboratory gain hands-on experience in a wide variety of molecular, genetic, histological, microscopic, and biochemical techniques, and are actively involved in not only project conception and execution, but also dissemination of results and findings through conference presentations and authorships on peer-reviewed manuscripts.

Project Narrative Heart and/or skeletal muscle defects in newborn infants remain the most prevalent form of human birth defects, yet the exact genes and genetic processes that can either positively or negatively affect muscle development remain unknown. Studies on Akirin, a nuclear protein that is found in both fruit flies and humans, have indicated that Akirin works with a novel class of regulators to facilitate heart and skeletal muscle development By studying the role of Akirin during this process in fruit fly embryos, we will learn how this protein likely functions in vertebrates, such as mammals, during heart formation.