XB-ART-56552Dev Cell January 1, 2019; 51 (6): 675-683.e4.
Isl1 Regulation of Nkx2.1 in the Early Foregut Epithelium Is Required for Trachea-Esophageal Separation and Lung Lobation.
The esophagus and trachea arise from the dorsal and ventral aspects of the anterior foregut, respectively. Abnormal trachea-esophageal separation leads to the common birth defect esophageal atresia with or without trachea-esophageal fistula (EA/TEF). Yet the underlying cellular mechanisms remain unknown. Here, we combine Xenopus and mouse genetic models to identify that the transcription factor Isl1 orchestrates trachea-esophageal separation through modulating a specific epithelial progenitor cell population (midline epithelial cells [MECs], Isl1+ Nkx2.1+ Sox2+) located at the dorsal-ventral boundary of the foregut. Lineage tracing experiments show that MECs contribute to both tracheal and esophageal epithelium, and Isl1 is required for Nkx2.1 transcription in MECs. Deletion of the chromosomal region spanning the ISL1 gene has been found in patients with abnormal trachea-esophageal separation. Our studies thus provide definitive evidence that ISL1 is a critical player in the process of foregut morphogenesis, acting in a small progenitor population of boundary cells.
PubMed ID: 31813798
PMC ID: PMC6919560
Article link: Dev Cell
Genes referenced: isl1 shh sox2 sox9 tp63
GO keywords: foregut morphogenesis
Morpholinos: Isl1 MO Mrpl24 MO Ovol2 MO Sall1 MO
Article Images: [+] show captions
|Figure 2. Deletion of Isl1 Leads to EA/TEF and Fusion of Right Lung Lobes (A) Isl1 expression is lost in the foregut epithelium but not mesenchyme of Shh-Cre; Isl1loxp/loxp mutants. (B) Isl1 deletion causes EA/TEF Formation in Approximately 50% Mutants (n = 18/36) (C) Isl1 deletion results in fusion of all four right lung lobes in all Shh-Cre; Isl1loxp/loxp mutants (n = 36/36). Note expression of airway and alveolar epithelium markers seems unperturbed in the mutant lung (n = 5). Abbreviations: Cr, cranial lobe; Ac, accessory lobe; Mi, middle lobe; Ca, caudal lobe. Scale bar: 50 μm. See also Figures S2 and S3.|
|Figure 3. Nkx2.1+ Lineage-Derived Cells Contribute to the Esophagus (A) The epithelium at the dorsal-ventral boundary (arrows) co-expresses Sox2 and Nkx2.1. (B) Sox2+ Nkx2.1+ epithelial cells (arrow) are present in the septum and forming esophagus. (C) Presence of a few Sox2+ Nkx2.1+ epithelial cells (arrow) in the ventral epithelium of the nascent esophagus. (D) Sox2+ Isl1+ epithelial cells (arrow) are present in the septum and forming esophagus. (E) Nkx2.1-CreER lineage labeled cells contribute to the ventral epithelium of the esophagus. A single dose of Tamoxifen induces Xgal+ cells in one location (arrow). (F) Lineage labeled cells are present in the ventral epithelium (arrows) of the esophagus. (G) Two doses of Tamoxifen induce Xgal+ cells in two separate locations (arrows). Abbreviations: V, ventral; D, dorsal; Tmx, tamoxifen. Scale bar: 50 μm. See also Figure S4.|
References [+] :
Ahlgren, Independent requirement for ISL1 in formation of pancreatic mesenchyme and islet cells. 1997, Pubmed