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Here we examined murine foregut septation in the <jats:italic>cobblestone<\/jats:italic> mutant, a hypomorphic allele of the gene encoding the intraflagellar transport protein IFT88, a protein essential for normal cilia function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We reveal a crucial role for primary cilia in foregut division, since their dramatic decrease in cilia in both the foregut endoderm and mesenchyme of mutant embryos resulted in a proximal tracheoesophageal septation defects and in the formation of distal tracheo(broncho)esophageal fistulae similar to the most common congenital tracheoesophageal malformations in humans. Interestingly, the dorsoventral patterning determining the dorsal digestive and the ventral respiratory endoderm remained intact, whereas Hedgehog signaling was aberrantly activated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate the <jats:italic>cobblestone<\/jats:italic> mutant to represent one of the very few mouse models that display both correct endodermal dorsoventral specification but defective compartmentalization of the proximal foregut. It stands exemplary for a tracheoesophageal ciliopathy, offering the possibility to elucidate the molecular mechanisms how primary cilia orchestrate the septation process. The plethora of malformations observed in the <jats:italic>cobblestone<\/jats:italic> embryo allow for a deeper insight into a putative link between primary cilia and human VATER\/VACTERL syndromes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/dvdy.660","type":"journal-article","created":{"date-parts":[[2023,9,30]],"date-time":"2023-09-30T07:35:52Z","timestamp":1696059352000},"page":"312-332","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Primary cilia are critical for tracheoesophageal septation"],"prefix":"10.1002","volume":"253","author":[{"given":"Lindsey Avery","family":"Fitzsimons","sequence":"first","affiliation":[{"name":"Graduate School of Biomedical Sciences and Engineering University of Maine  Orono Maine USA"},{"name":"Department of Biomedical Sciences Center for Excellence in the Neurosciences, College of Osteopathic Medicine, University of New England  Biddeford Maine USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelia","family":"Tasouri","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center for Neurosciences University of Heidelberg  Heidelberg Germany"},{"name":"Institute of Anatomy and Cell Biology University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc August","family":"Willaredt","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center for Neurosciences University of Heidelberg  Heidelberg Germany"},{"name":"Institute of Anatomy and Cell Biology University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Stetson","sequence":"additional","affiliation":[{"name":"AstraZeneca Pharmaceuticals LP  Waltham Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Gojak","sequence":"additional","affiliation":[{"name":"Interdisciplinary Center for Neurosciences University of Heidelberg  Heidelberg Germany"},{"name":"Institute of Anatomy and Cell Biology University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Kirsch","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology University of Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Humphrey A. 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