AI Insight
This study reveals that human foregut development combines mouse-like molecular patterning with chick-like epithelial tissue architecture, explaining why mouse models poorly replicate the most common human birth defect of the esophagus and trachea (EA/TEF). Through comparative analysis across species and live imaging, researchers found that humans and chicks share a densely packed, pseudostratified epithelial structure with different contractile protein expression than mice, leading to slower tissue separation during development. By experimentally inducing similar defects in chick embryos through BMP signaling manipulation, the team demonstrated that the chick may serve as a better model than mice for studying these human malformations.
Why it matters
These findings could improve our ability to understand and potentially prevent esophageal atresia with tracheoesophageal fistula, a serious birth defect affecting approximately 1 in 3,500 births. The identification of chick embryos as a more appropriate model system for this condition may accelerate research into prevention strategies and therapeutic interventions.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Animal models are indispensable for understanding human development, yet evolutionary relatedness does not ensure developmental similarity at all biological scales. In tracheal-esophageal separation (TES), which splits the embryonic foregut into respiratory and digestive tubes in all tetrapods, genetic mouse models rarely reproduce the predominant human malformation, esophageal atresia with tracheoesophageal fistula (EA/TEF). By comparing human, mouse, and chick foreguts, we uncover a mosaic pattern of developmental conservation. The human foregut resembles the mouse in its molecular patterning, but more closely resembles the chick in its densely pseudostratified epithelial architecture and the greater number of cells comprising the epithelial septum. Live imaging shows that epithelial pseudostratification, which depends on actomyosin contractility, is associated with slower septum resolution. Cross-species single-cell transcriptomics analysis reveals lower expression of a myosin regulatory light chain and N-cadherin, and higher expression of a myosin phosphatase subunit in the mouse foregut epithelium than in the human and chick, suggesting candidate molecular mechanisms of these morphological differences. Induction of ectopic BMP signaling through in vivo electroporation in chick embryos recapitulated an EA/TEF-like malformation. These findings suggest that human foregut morphogenesis combines murine-like patterning and avian-like epithelial organization. The chick embryo thus represents an important complementary model for investigating epithelial mechanisms underlying human foregut malformations.