Molecular Pathways and Animal Models of Tricuspid Atresia and Univentricular Heart

• Published in: Advances in experimental medicine and biology Vol. 1441; p. 885
• Main Authors: Shibbani, Kamel, Nemer, George
• Format: Journal Article
• Language: English
• Published: United States 2024
• Subjects: Animals; Disease Models, Animal; Humans; Mice; NFATC Transcription Factors - genetics; NFATC Transcription Factors - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Signal Transduction; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Tricuspid Atresia - genetics; Tricuspid Atresia - metabolism; Tricuspid Atresia - pathology; Univentricular Heart - genetics; Univentricular Heart - metabolism; Univentricular Heart - pathology; Univentricular Heart - physiopathology; NFATC1Nuclear factor of activated T-cells (NFAT); BMP; TGF-ß; Transforming growth factor; VEGF; Mutant mice; NOTCH; Epithelial–mesenchymal transition; Looping; TBX5; EMT; TA; Tricuspid atresia; GATA4GATA binding protein (GATA)GATA4; Trisomy 16; Univentricular heart; AV canal; SOX9SRY (sex determining region Y)-box (SOX)SOX9; Mesenchymal cells; SMAD4SMAD family member (SMAD)SMAD4; Atrioventricular canal; HEY2; NKX2-5
• ISSN: 0065-2598
• DOI: 10.1007/978-3-031-44087-8_55

The process of valve formation is a complex process that involves intricate interplay between various pathways at precise times. Although we have not completely elucidated the molecular pathways that lead to normal valve formation, we have identified a few major players in this process. We are now able to implicate TGF-ß, BMP, and NOTCH as suspects in tricuspid atresia (TA), as well as their downstream targets: NKX2-5, TBX5, NFATC1, GATA4, and SOX9. We know that the TGF-ß and the BMP pathways converge on the SMAD4 molecule, and we believe that this molecule plays a very important role to tie both pathways to TA. Similarly, we look at the NOTCH pathway and identify the HEY2 as a potential link between this pathway and TA. Another transcription factor that has been implicated in TA is NFATC1. While several mouse models exist that include part of the TA abnormality as their phenotype, no true mouse model can be said to represent TA. Bridging this gap will surely shed light on this complex molecular pathway and allow for better understanding of the disease process.