Yap And Taz Are Required For Neural Crest-Derived Cardiovascular Development

Author

Shannon ErhardtFollow

Author ORCID Identifier

0000-0002-0189-0012

Date of Graduation

8-2022

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Jun Wang, PhD

Committee Member

Richard Behringer, PhD

Committee Member

Peter Lwigale, PhD

Committee Member

James Martin, MD, PhD

Committee Member

Rachel Miller, PhD

Abstract

Congenital heart defects (CHDs) are the most common human birth defect, occurring in ~1/100 newborns, and are a leading cause of early infant death. Cardiac neural crest cells (NCCs) are a migratory and multipotent cell population known to aid in the development of the cardiac outflow tract (OFT), valves, and interventricular septum, during embryogenesis. Yap and Taz are downstream effectors of the fundamental Hippo signaling pathway and are vital for proper organ and tissue development, yet their role in neural crest (NC)-derived heart formation is still largely unknown. We generated Yap and Taz conditional knockout (CKO) mice using a Cre-lox system, by the use of Yap and Taz CKO alleles and the NC-specific Cre drivers Wnt1-Cre and Wnt1-Cre2SOR, which leads to abnormal cardiac formation, mimicking human CHD phenotypes. Yap^+/-; Taz^-/- CKO mutants produced various OFT and remodeling defects including ventricular septal defect (VSD), tetralogy of Fallot (TOF), double outlet right ventricle (DORV), and cardiac valve aberrations, varyingly between embryonic day (E) 14.5, E16.5, and E18.5. Cell apoptosis, proliferation, and smooth muscle differentiation were unchanged in Yap^+/-; Taz^-/- CKO mutants. Comparably, Yap^+/-; Taz^+/- double heterozygous hearts exhibited external morphology similar to that of controls, but sectioning revealed mild VSD, along with cardiac valve leaflet irregularities, at E16.5 and E18.5. Compelling preliminary RNA-sequencing data together with transwell migration assay, scratch assay, and ex vivo culture, indicate a potential role for Yap/Taz in regulating NC migration. Together, our data indicate that Yap/Taz play a critical role in proper cardiac NC-derived cardiac formation.

Keywords

neural crest cells, congenital heart defects, heart development, embryogenesis, Hippo signaling pathway, Yap and Taz