Noggin regulates foregut progenitor cell programming, and misexpression leads to esophageal atresia
Carolina Pinzon-Guzman, … , Scott D. Boden, James R. Goldenring
Carolina Pinzon-Guzman, … , Scott D. Boden, James R. Goldenring
Published May 19, 2020
Citation Information: J Clin Invest. 2020;130(8):4396-4410. https://doi.org/10.1172/JCI123597.
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Noggin regulates foregut progenitor cell programming, and misexpression leads to esophageal atresia

Abstract

Esophageal atresia (EA/TEF) is a common congenital abnormality present in 1 of 4000 births. Here we show that atretic esophagi lack Noggin (NOG) expression, resulting in immature esophagus that contains respiratory glands. Moreover, when using mouse esophageal organoid units (EOUs) or tracheal organoid units (TOUs) as a model of foregut development and differentiation in vitro, NOG determines whether foregut progenitors differentiate toward esophageal or tracheal epithelium. These results indicate that NOG is a critical regulator of cell fate decisions between esophageal and pulmonary morphogenesis, and its lack of expression results in EA/TEF.

Authors

Carolina Pinzon-Guzman, Sreedhara Sangadala, Katherine M. Riera, Evgenya Y. Popova, Elizabeth Manning, Won Jae Huh, Matthew S. Alexander, Julia S. Shelton, Scott D. Boden, James R. Goldenring

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Figure 4

Cultured murine foregut progenitors change fate depending on presence of NOG.

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Cultured murine foregut progenitors change fate depending on presence of...
(A) mEOUs cultured for 10 days. NOG inhibitor was added to the culture for 48 hours, washed, and cultures allowed to grow for 10 days. Tissue was embedded in paraffin and slides analyzed with IHC for expression of esophageal and tracheal markers. (B) Fluorescence intensity of NOG, BMP4, CK13, TFF3, CC10, and CK4 was evaluated using Image J. mEOUs from 6 different litters (n = 4–12). (C) P1–P3 murine trachea were collected to generate TOUs. TOUs were cultured for 10 days with or without NOG, fixed, and paraffin sections were used to evaluate their morphology and protein expression. (D) Fluorescence intensity of NOG, BMP4, CK13, TFF3, CC10, and CK4 was evaluated using Image J. mTOUs from 5 different litters (n = 3–5). Scale bars: 100 μm. There was no change in the expression of SOX2 or SHH. *P < 0.05, **P < 0.005, ***P < 0.0009.