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SMAD6 is required for normal foregut development in humans and frogs
Vivien Pagan1,2,3,4, Scott A Rankin1,2, Nicole A Edwards1,2
1Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Development (Cambridge, England)
|August 14, 2026
Summary
Rare variants in SMAD6 cause foregut malformations like esophageal atresia/tracheoesophageal fistula (EA/TEF). Loss of SMAD6 disrupts embryonic development, leading to these congenital conditions.
Area of Science:
- Developmental Biology
- Genetics
- Stem Cell Biology
Background:
- Esophageal atresia/tracheoesophageal fistula (EA/TEF) are congenital foregut malformations.
- The BMP/TGFβ repressor SMAD6 is implicated in these conditions through identified patient variants.
Purpose of the Study:
- To investigate the role of SMAD6 in tracheoesophageal development.
- To explore SMAD6 function in human foregut epithelium and mesenchyme.
Main Methods:
- Utilized Xenopus embryos for functional studies of SMAD6.
- Employed human pluripotent stem cell-derived foregut tissues.
- Performed CRISPR-mediated disruption of SMAD6 in human cells.
Main Results:
- Loss of SMAD6 led to foregut malformations in Xenopus embryos.
- SMAD6 disruption increased BMP signaling and caused patterning defects in human foregut tissues.
- SMAD6 deficiency impaired endothelial cell formation in mesenchyme.
Conclusions:
- SMAD6 is essential for proper foregut development.
- Genetic variants in SMAD6 are likely causative for EA/TEF in affected patients.
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