Defining the role of Pou6f1 in cardiac morphogenesis

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Defining the role of Pou6f1 in cardiac morphogenesis PROJECT SUMMARY Congenital heart disease (CHD) is the leading cause of birth defects and continues to carry a poor long-term prognosis despite marked improvements in contemporary management. This failure stems from severely lim- ited diagnostic capabilities coupled with a complete inability to modify the underlying disease process. Alt- hough the transcriptional pathways responsible for heart development have been well-characterized, new regulators of the established circuitry are urgently needed to identify novel CHD candidate loci and illuminate potential therapeutic targets. The long-term goal of this research program is to understand transcriptional con- trol of cardiac lineage specification using atrioventricular canal (AVC) differentiation as a model system. The objective of this proposal is to characterize a recently identified upstream regulator of AVC specification. Our central hypothesis is that Pou6f1 regulates cardiac structure and function. To test this hypothesis, we propose the following specific aims: 1) Analyze cardiac phenotypes resulting from Pou6f1 over-expression and 2) De- termine the impact of Pou6f1 deletion on cardiac function. Our preliminary data indicate that cardiac-specific over-expression of dominant-negative Pou6f1 perturbs AVC morphogenesis and results in embryonic lethality. In Aim 1, we will examine the consequences of Pou6f1 gain-of-function during heart development by utilizing two mouse lines for tissue-specific Pou6f1 over-expression that we have generated in our lab. Additional pre- liminary results show that global Pou6f1 deletion causes male-specific embryonic lethality and cardiomyopathy in surviving females. In Aim 2, we will evaluate the functional consequences of global and cardiac-specific Pou6f1 deletion using a floxed allele that we have previously obtained. Our approach is innovative because it will challenge and expand the existing paradigm for AVC morphogenesis, a critical step for proper formation of the atrial septum, ventricular septum, and AV valves. This project is significant, therefore, because it will impli- cate an entirely new transcriptional pathway in AVC specification and cardiac morphogenesis. Taken togeth- er, the expected benefits from the proposed studies are to establish a role for Pou6f1 during cardiac morpho- genesis and to obtain key preliminary data for a competitive R01 submission. We anticipate that subsequent follow-up studies will provide a more informed mechanistic understanding of AVC morphogenesis. In turn, such insights promise to expand the list of candidate loci and provide a platform for the rational design of novel treatments for AVSDs.