Congenital heart disease (CHD) is the most common birth defect?occurring in as many as 3 in every 100 live births. Despite its frequency, the genetic etiologies of CHD remain elusive due to prevalent contribution of noncoding variation and genetic modifiers. As a lab we attempt to distill this complexity though understanding the underlying gene regulatory networks involved in CHD. In this study, we uncover a gene regulatory network essential for the proper development of cardiovascular lineages downstream of the hedgehog (hh) signaling, a master regulator of cell fate determination. Our previous work has shown that Hedgehog signaling is required for second heart field-derived cardiac structures. Using Genetic Inducible Fate Mapping, we observed that late labeling of cardiac progenitors (E8.5 and later) labeled only second heart field structures while early labeling of cardiac progenitors (E6.5) additionally labeled first heart field derived structures. Germline removal of all hh signaling, through ablation of a key membrane-bound receptor, smoothened (smo), caused hypoplasia of the linear heart tube, a failure of chamber expansion, and early embryonic lethality. Conditional smo removal using Mesp1-Cre recapitulated the germline phenotype whereas smo removal using Nxk2-5-Cre supported chamber formation, restricting the requirement for hh signaling to early mesoderm. RNA-seq of Mesp1+ cells overexpressing Gli3R, the primary hh-signaling transcriptional repressor revealed upregulation of lineage- determining transcriptional programs for differentiating cardiovascular lineages at embryonic day 7.5 but down- regulation of factors involved with maintenance of progenitor identity. We hypothesize that hedgehog signaling controls a gene regulatory network required for the proper establishment of cardiovascular lineages by controlling the differentiation timing of mesodermal progenitors. As a means to accomplish this, we propose to 1) Validate and study the developmental mechanisms of transcriptional disruption of cell fate decisions in the cardiogenic mesoderm 2) Study the cellular and mechanistic basis for the severe hypoplastic cardiac defects caused by disruption in early hh singaling. These data will be integrated as a means to understand not only the mechanism by which hh controls early mesodermal patterning, but to contribute foundational knowledge towards the elucidation of CHD etiology by providing a novel mechanism for hypoplastic cardiac phenotypes.

Public Health Relevance

Congenital heart disease (CHD) is the most common birth defect?occurring in as many as 3 out of every 100 live births resulting in an enormous burden to public health. Despite extensive effort in the field, many CHDs are never assigned a clear genetic etiology due to obfuscation by genetic modifiers, rare mutations, and non- coding regulatory variation. This proposal aims to elaborate a mechanistic framework for understanding the complex genetics of CHD through investigation of an essential cardiac gene regulatory network which will inform our understanding of how to diagnose, stratify, and manage life-long treatment for CHD patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Meadows, Tawanna
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University of Chicago
Schools of Medicine
United States
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