The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling
Cardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor Sox7 has critical functions in the vascular development and angiogenesis. It is unclear whether Sox7 also contributes to cardiac septation development. We identified a de novo 8p23.1...
Gespeichert in:
Veröffentlicht in: | Cell death & disease 2021-04, Vol.12 (4), p.393-393, Article 393 |
---|---|
Hauptverfasser: | , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Cardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor
Sox7
has critical functions in the vascular development and angiogenesis. It is unclear whether
Sox7
also contributes to cardiac septation development. We identified a de novo 8p23.1 deletion with
Sox7
haploinsufficiency in an atrioventricular septal defect (AVSD) patient using whole exome sequencing in 100 AVSD patients. Then, multiple
Sox7
conditional loss-of-function mice models were generated to explore the role of
Sox7
in atrioventricular cushion development.
Sox7
deficiency mice embryos exhibited partial AVSD and impaired endothelial to mesenchymal transition (EndMT). Transcriptome analysis revealed BMP signaling pathway was significantly downregulated in
Sox7
deficiency atrioventricular cushions. Mechanistically,
Sox7
deficiency reduced the expressions of
Bmp2
in atrioventricular canal myocardium and
Wnt4
in endocardium, and
Sox7
binds to
Wnt4
and
Bmp2
directly. Furthermore, WNT4 or BMP2 protein could partially rescue the impaired EndMT process caused by
Sox7
deficiency, and inhibition of BMP2 by Noggin could attenuate the effect of WNT4 protein. In summary, our findings identify
Sox7
as a novel AVSD pathogenic candidate gene, and it can regulate the EndMT involved in atrioventricular cushion morphogenesis through Wnt4–Bmp2 signaling. This study contributes new strategies to the diagnosis and treatment of congenital heart defects. |
---|---|
ISSN: | 2041-4889 2041-4889 |
DOI: | 10.1038/s41419-021-03658-z |