J Pediatr Surg
. 2026 Feb 12:163010.
doi: 10.1016/j.jpedsurg.2026.163010. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/41690377/
CITED2 deficiency drives pulmonary hypoplasia via miR-200b and inflammatory pathways
Marietta Jank 1, Marija Kuna 2, Jackie Wang 3, Jacquelyn Schwartz 3, Yuichiro Miyake 4, Sakika Shimzu 4, Rina Tanaka 3, Muntahi Mourin 3, Jai Sareen 3, Arzu O Aptekmann 3, Daywin Patel 3, Michael Boettcher 5, Michael J Soares 2, Richard Keijzer 6
Affiliations Expand
- PMID: 41690377
- DOI: 10.1016/j.jpedsurg.2026.163010
Free article
Abstract
Background: CITED2 is a transcriptional co-activator with widespread roles in development. We recently found that the nitrofen rat model of congenital diaphragmatic hernia (CDH) showed CITED2 dysregulation at a late stage of abnormal lung development, but the role of CITED2 in lung development remains unexplored. Here, we study potential pathways of CITED2 in multiple models of lung hypoplasia.
Methods: We used CRISPR/Cas9-generated CITED2-deficient rats to examine fetal lung growth, lung morphometry and inflammatory gene expression. CITED2 and its potential up- and downstream mediators were also assessed in human CDH lungs, nitrofen-induced CDH rats, and miR-200b knockout mice.
Results: CITED2-deficient rats had signs of lung hypoplasia (reduced lung weights and smaller alveoli) but macroscopically intact diaphragms. Lung tissues from human CDH patients showed upregulated CITED2 abundance and chromosomal alterations at its locus. We identified miR-200b as a regulator of CITED2, with miR-200b knockout mice demonstrating increased Cited2 expression. We also identified SoxC family transcription factors as potential downstream mediators of CITED2’s effect on lung development, with Sox4, Sox11, and Sox12 downregulated in a rat nitrofen model of CDH, but Sox4 and Sox11 upregulated in CITED2-deficient rats. CITED2 deficiency further led to increased pulmonary Nfκb and decreased Il1β expression.
Conclusion: Our data suggest that CITED2 is crucial for fetal lung development, alveolar structure and balanced inflammatory signaling. Both under- (Cited2-/-) and overexpression (CDH) of CITED2 result in lung hypoplasia. SoxC family transcription factors were dysregulated in both models of abnormal lung development, which may be related to downstream changes in inflammatory cytokine expression. Evidence supports miR-200b as an upstream regulator of CITED2, which can be targeted in future studies of abnormal lung development and CDH.
Keywords: Abnormal lung development; CITED2; Congenital diaphragmatic hernia; Lung hypoplasia.
Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.
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