Nkx2.7 is a conserved regulator of craniofacial development
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 con...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58821-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Caitlin Ford |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-758e5198963e4ddf8a56c8a80d178d38 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-758e5198963e4ddf8a56c8a80d178d382025-08-20T03:15:09ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-58821-3Nkx2.7 is a conserved regulator of craniofacial developmentCaitlin Ford0Carmen de Sena-Tomás1Tint Tha Ra Wun2Angelika G. Aleman3Uday Rangaswamy4Jake Leyhr5María I. Nuñez6Cynthia Zehui Gao7Hieu T. Nim8Michael See9Ugo Coppola10Joshua S. Waxman11Mirana Ramialison12Tatjana Haitina13Joanna Smeeton14Remo Sanges15Kimara L. Targoff16Department of Genetics & Development, College of Physicians & Surgeons, Columbia UniversityDivision of Cardiology, Department of Pediatrics, College of Physicians & Surgeons, Columbia UniversityDivision of Cardiology, Department of Pediatrics, College of Physicians & Surgeons, Columbia UniversityDivision of Cardiology, Department of Pediatrics, College of Physicians & Surgeons, Columbia UniversityFunctional and Structural Genomics, Scuola Internazionale Superiore di Studi Avanzati (SISSA)Department of Organismal Biology, Uppsala UniversityDivision of Cardiology, Department of Pediatrics, College of Physicians & Surgeons, Columbia UniversityDivision of Cardiology, Department of Pediatrics, College of Physicians & Surgeons, Columbia UniversityThe Novo Nordisk Foundation Center for Stem Cell Medicine & Stem Cell Biology, Murdoch Children’s Research InstituteThe Novo Nordisk Foundation Center for Stem Cell Medicine & Stem Cell Biology, Murdoch Children’s Research InstituteMolecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children’s Hospital Medical CenterMolecular Cardiovascular Biology Division and Heart Institute, Cincinnati Children’s Hospital Medical CenterThe Novo Nordisk Foundation Center for Stem Cell Medicine & Stem Cell Biology, Murdoch Children’s Research InstituteDepartment of Organismal Biology, Uppsala UniversityDepartment of Genetics & Development, College of Physicians & Surgeons, Columbia UniversityFunctional and Structural Genomics, Scuola Internazionale Superiore di Studi Avanzati (SISSA)Division of Cardiology, Department of Pediatrics, College of Physicians & Surgeons, Columbia UniversityAbstract 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.https://doi.org/10.1038/s41467-025-58821-3 |
| spellingShingle | 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 Nkx2.7 is a conserved regulator of craniofacial development Nature Communications |
| title | Nkx2.7 is a conserved regulator of craniofacial development |
| title_full | Nkx2.7 is a conserved regulator of craniofacial development |
| title_fullStr | Nkx2.7 is a conserved regulator of craniofacial development |
| title_full_unstemmed | Nkx2.7 is a conserved regulator of craniofacial development |
| title_short | Nkx2.7 is a conserved regulator of craniofacial development |
| title_sort | nkx2 7 is a conserved regulator of craniofacial development |
| url | https://doi.org/10.1038/s41467-025-58821-3 |
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