Investigating the role of Yap/Taz in neural crest-derived cardiac development

Project Summary/Abstract Congenital heart defects (CHDs) are the most common human birth defect. Although CHDs are highly prevalent, knowledge regarding disease onset is currently limited, restricting therapeutic progression. CHDs can arise due to the altered contribution of cardiac progenitor cell populations, including cardiac neural crest cells (NCCs), a vital migratory and multipotent cell population for proper mammalian heart formation. The fundamental Hippo signaling pathway is crucial in regulating heart development and homeostasis. Patient data and animal models have indicated that changes in Hippo signaling result in various types of CHDs. The canonical Hippo downstream effectors Yap and Taz are essential for NCC regulation throughout the developing embryo, yet their role in NCC-derived heart development remains unknown. I maintain a mouse cohort with a Cre recombinase conditional deletion of Yap/Taz in the NCC population and found that Yap/Taz deficiencies in NCCs result in external and internal cardiac defects, creating a CHD mouse model. Furthermore, I identified that deficiencies of Yap/Taz reduced cardiac outflow tract (OFT) cell migration capabilities ex vivo and in vitro. This project aims to define how mutant Hippo signaling drives the dysregulation of NC and cardiac development. I hypothesize that the Hippo signaling effectors Yap/Taz regulate proper cardiac remodeling during NCC-derived heart development. Aim 1 will investigate the role of Yap/Taz in cardiac OFT development by characterizing altered cellular composition due to Yap/Taz deficiencies and performing sc-multi-omics on control and Yap/Taz deficient cardiac OFTs. Aim 2 will explore the mechanism underlying Hippo-regulated NCC differentiation and its impact on cardiac tissue stiffness both in vivo and in vitro. This project will elucidate the roles of Hippo signaling in NCC-derived heart development. Findings from these proposed studies will shed light on the molecular mechanisms regulating heart development and help develop novel diagnostic and therapeutic strategies for CHDs.