| Autor: |
Nasr, Talia, Holderbaum, Andrea M., Chaturvedi, Praneet, Agarwal, Kunal, Kinney, Jessica L., Daniels, Keziah, Trisno, Stephen L., Ustiyan, Vladimir, Shannon, John M., Wells, James M., Sinner, Debora, Kalinichenko, Vladimir V., Zorn, Aaron M. |
| Zdroj: |
Disease Models and Mechanisms; 2021, Vol. 14 Issue: 2 pdmm046573-dmm046573, 1p |
| Abstrakt: |
ABSTRACTCongenital tracheomalacia, resulting from incomplete tracheal cartilage development, is a relatively common birth defect that severely impairs breathing in neonates. Mutations in the Hedgehog (HH) pathway and downstream Gli transcription factors are associated with tracheomalacia in patients and mouse models; however, the underlying molecular mechanisms are unclear. Using multiple HH/Glimouse mutants, including one that mimics Pallister–Hall Syndrome, we show that excessive Gli repressor activity prevents specification of tracheal chondrocytes. Lineage-tracing experiments show that Sox9+chondrocytes arise from HH-responsive splanchnic mesoderm in the fetal foregut that expresses the transcription factor Foxf1. Disrupted HH/Gli signaling results in (1) loss of Foxf1, which in turn is required to support Sox9+chondrocyte progenitors, and (2) a dramatic reduction in Rspo2, a secreted ligand that potentiates Wnt signaling known to be required for chondrogenesis. These results reveal an HH-Foxf1-Rspo2 signaling axis that governs tracheal cartilage development and informs the etiology of tracheomalacia.This article has an associated First Person interview with the first author of the paper. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
