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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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Research Article Development Article has an altmetric score of 15

Noggin regulates foregut progenitor cell programming, and misexpression leads to esophageal atresia

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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 3

N-50 is a small molecule that inhibits NOG in vitro.

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N-50 is a small molecule that inhibits NOG in vitro.
(A) Validation of a...
(A) Validation of a BMP2 reporter assay and selection of optimal BMP-NOG ratio for compound screening (1:6 ratio is chosen). The dose-dependent inhibition by NOG of BMP2-induced luciferase activity in C2C12 cells transfected with BMP-specific and Smad1-driven 9 × GCCG reporter plasmid. The reporter responded dose dependently to BMP2. Data points of luciferase activities were determined in triplicate cell culture wells (n = 3). The error bar represents SEM. Statistical significance (P < 0.05) was determined by 1-way ANOVA between the controls and treatments. (B) N-50 inhibition increases BMP efficacy in addition to reversing the effects of exogenously added NOG. N-50 was the most potent enhancer above baseline, increasing BMP2 responsiveness 2-fold (tallest green bar). The enhancement above the baseline BMP2 luciferase response (100%) suggests that N-50 was the best compound to also inhibit endogenous NOG and reverse the effects of exogenously added NOG. Luciferase activities were determined in triplicate. Error bars (±SEM) from triplicate determinations (n = 3) from cell-culture wells. The BMP+NOG group was compared with all other treatment groups using 1-way ANOVA, and statistical significance of P < 0.05 was determined between the control and treatments. Compounds that exhibited undesired effects on cell growth and morphology were dropped from further analyses. (C) In vitro binding assay with purified recombinant BMP2 and NOG proteins. NOG and BMP2 were labeled with biotin and 125iodine, respectively. Constant amounts of biotin-labeled NOG and 125iodine-labeled BMP2 were incubated with or without varying concentrations of unlabeled BMP2 or N-50 as described in Methods. Biotin-labeled NOG was pulled down with neutravidin-agarose beads and the counts associated with pellets were counted. The chemical 2-vinyl-4,6-diamino-1,3,5-triazine was designed as the control based on a different target structure expected not to interfere with BMP-NOG binding.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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