Year: 2025
Type: article
Abstract: Craniofacial malformations arise from developmental defects in the head, face, and neck with phenotypes such as 22q11.2 deletion syndrome illustrating a developmental link between cardiovascular and craniofacial morphogenesis. NKX2-5 is a key cardiac transcription factor associated with congenital heart disease and mouse models of Nkx2-5 deficiency highlight roles in cardiac development. In zebrafish, nkx2.5 and nkx2.7 are paralogues in the NK4 family expressed in cardiomyocytes and pharyngeal arches. Despite shared cellular origins of cardiac and craniofacial tissues, the function of NK4 factors in head and neck patterning has not been elucidated. Molecular evolutionary analysis of NK4 genes shows that nkx2.5 and nkx2.7 are ohnologs resulting from whole genome duplication events. Nkx2.7 serves as a previously unappreciated regulator of branchiomeric muscle and cartilage formation for which nkx2.5 cannot fully compensate. Mechanistically, our results highlight that Nkx2.7 patterns the cranial neural crest and functions upstream of Endothelin1 to inhibit Notch signals. Together, our studies shed light on an evolutionarily conserved Nkx transcription factor with unique functions in vertebrate craniofacial development, advancing our understanding of congenital head and neck deformities. Craniofacial malformations have been linked to congenital heart defects, as in 22q11.2 deletion syndrome, but the mechanisms linking these lineages remain unknown. Here they show that zebrafish nxk2.7 is expressed in cardiopharyngeal progenitors and has roles in craniofacial development that cannot be compensated for by nkx2.5.
Source: Nature Communications
Authors: Caitlin Ford, Carmen de Sena-Tomás, Tint Tha Ra Wun, Angelika G. Aleman, Uday Rangaswamy, Jake Leyhr, María I. Nuñez, Cynthia Zehui Gao, Hieu T. Nim, Michael See, Ugo Coppola, Joshua S. Waxman, Mirana Ramialison, Tatjana Haitina, Joanna Smeeton, Remo Sanges, Kimara L. Targoff
Institutions: Columbia University, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de Barcelona, Memorial Sloan Kettering Cancer Center, Scuola Internazionale Superiore di Studi Avanzati, Uppsala University, The University of Melbourne, Australian Regenerative Medicine Institute, Murdoch Children's Research Institute, Monash University, Cincinnati Children's Hospital Medical Center, Florida Gulf Coast University, University of Cincinnati, Columbia University Irving Medical Center, Italian Institute of Technology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1314074292, G1969964321, G2584391057, G2868715016, G3080360182, Mechanisms of second heart field development regulated by Nkx genes, Cardiac Transcription Factor Nkx2.7 is a Novel Regulator of Craniofacial Development, Essential functions of Fibulin proteins in outflow tract morphogenesis., G6609150140
OpenAlex ID: W4409696474