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Transcriptional Regulation of Tracheoesophageal Fate Specification in the Mammalian Foregut


Specification of the trachea and esophagus from the embryonic foregut is critical for the function of the respiratory and digestive systems. Congenital birth defects associated with improper tracheoesophageal development in humans are common and have severe consequences to respiration and feeding that require immediate surgical intervention. During development, tracheoesophageal specification is dependent on proper dorsoventral patterning of the foregut endoderm tube. This involves the establishment of ventral NKX2.1 and dorsal SOX2 expression domains that are thought to promote tracheal and esophageal fate, respectively. Loss of Nkx2.1 results in failed foregut separation, and adoption of SOX2 expression throughout the common foregut tube. Similarly, loss of Sox2 results in a common foregut tube expressing NKX2.1, leading to the previous conclusion that both of these transcription factors are master regulators of tracheal and esophageal fate, respectively. However, our understanding of tracheoesophageal fate specification is limited by a lack of information on dorsoventral foregut patterning at the transcriptome level. In this study, we use genome-wide methods to understand how tracheal and esophageal lineages are specified during mouse embryonic development. We use single cell RNA-sequencing to define transcriptomic profiles of early developing mouse trachea, lung, and esophagus, and discover a multitude of previously unknown markers of these tissues. Transcriptomic analysis of Nkx2.1-/- mutant foreguts reveals that NKX2.1 loss does not result in lineage conversion to esophagus as previously hypothesized and exposes an NKX2.1-independent tracheoesophageal program. Using ChIP-seq against NKX2.1, we identify direct NKX2.1 regulatory targets and interrogate their combinatorial regulation by NKX2.1 and SOX2 in compound mouse mutant analysis. Amongst the novel targets we identify are Shh and Wnt7b, which we demonstrate are regulated by NKX2.1 to control tracheal and esophageal mesenchyme specification to cartilage and smooth muscle. Together, these data dramatically revise our understanding of how tracheal and esophageal cell types are specified during development and uncover a limited yet critical role for Nkx2.1 in this process.

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