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.
With an estimated incidence of 1 in 100 live births, congenital heart disease (CHD) is the leading cause of newborn birth defects. Nevertheless, most sporadic and many familial heart defects cannot be ex- plained by mutations in known candidates, and there are currently no FDA-approved medications to treat the underlying disease process. This project seeks to implicate an entirely novel transcriptional pathway in heart development, thereby providing new CHD candidate loci and potential targets for drug development.
| Bhakta, Minoti; Padanad, Mahesh S; Harris, John P et al. (2018) pouC Regulates Expression of bmp4 During Atrioventricular Canal Formation in Zebrafish. Dev Dyn : |
