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

<p>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. <em>Yap </em>and <em>Taz </em>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 <em>Yap </em>and <em>Taz </em>conditional knockout (CKO) mice using a Cre-lox system, by the use of <em>Yap </em>and <em>Taz </em>CKO alleles and the NC-specific Cre drivers <em>Wnt1-Cre </em>and <em>Wnt1-Cre2SOR, </em>which leads to abnormal cardiac formation, mimicking human CHD phenotypes. <em>Yap^+/-; Taz^-/- </em>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 <em>Yap^+/-; Taz^-/- </em>CKO mutants. Comparably, <em>Yap^+/-; Taz^+/- </em>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 <em>ex vivo </em>culture, indicate a potential role for <em>Yap/Taz</em> in regulating NC migration. Together, our data indicate that <em>Yap/Taz</em> play a critical role in proper cardiac NC-derived cardiac formation.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2022

Authors dc:creator

• Erhardt, Shannon
• <p>0000-0002-0189-0012</p>

Contributors dc:contributor

• Jun Wang, PhD
• Richard Behringer, PhD
• Peter Lwigale, PhD

• neural crest cells
• congenital heart defects
• heart development
• embryogenesis
• Hippo signaling pathway
• Yap and Taz
• Biology
• Cell and Developmental Biology
• Genetics and Genomics
• Medical Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1217

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2274