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Single-cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest
Christopher De Bono1, Yang Liu2, Alexander Ferrena2,3
1Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA. christopher.debono@einsteinmed.edu.
Nature Communications
|March 21, 2023
Summary
Tbx1 gene disruption in mouse embryos impairs cardiac neural crest cell differentiation into vascular smooth muscle cells, leading to congenital heart defects. Loss of Tbx1 affects cell signaling and dynamic transitions crucial for heart development.
Area of Science:
- Developmental Biology
- Genetics
- Cardiovascular Research
Background:
- Congenital heart disease (CHD) arises from disruptions in cardiac neural crest cells (CNCCs).
- The precise cell fate dynamics of CNCCs differentiating into vascular smooth muscle cells remain incompletely understood.
- Tbx1 gene mutations are associated with 22q11.2 deletion syndrome, a common cause of CHD.
Purpose of the Study:
- To investigate the role of Tbx1 in CNCC differentiation and its impact on heart development.
- To elucidate the cell fate transitions of pharyngeal NCCs towards smooth muscle lineages.
- To identify signaling pathways affected by Tbx1 loss during embryonic heart formation.
Main Methods:
- Single-cell RNA sequencing of mouse embryonic pharyngeal and cardiac neural crest cells (CNCCs).
- Comparative analysis between control embryos and those with Tbx1 gene inactivation.
- Inactivation of Tbx2 and Tbx3 in early CNCCs to assess their role in smooth muscle differentiation.
Main Results:
- Three dynamic cell fate transitions were identified in pharyngeal NCCs, involving Tbx2 and Tbx3 expression, leading to smooth muscle differentiation.
- Loss of Tbx1 non-autonomously altered these CNCC transitions.
- Tbx1 deficiency disrupted mesoderm-CNCC communication, affecting BMP and MAPK signaling pathways.
- Inactivation of Tbx2 and Tbx3 caused aortic arch branching defects due to failed smooth muscle differentiation.
- Tbx1 loss led to disrupted aortic arch artery formation and cardiac outflow tract septation.
Conclusions:
- Tbx1 is critical for normal CNCC differentiation into vascular smooth muscle cells, influencing cell-cell communication and signaling pathways.
- Altered dynamic transitions in CNCCs due to Tbx1 deficiency result in severe congenital heart defects, including aortic arch abnormalities and outflow tract septation issues.
- Tbx2 and Tbx3 play essential roles in smooth muscle differentiation and aortic arch development, downstream of Tbx1 signaling.
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