Abstract
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/Gli mouse 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.
Highlights
Impaired formation of the tracheal cartilage, or tracheomalacia, occurs in 1 in 2100 live births and can result in life-threatening airway collapse and impaired breathing (Boogaard et al, 2005; Kamran and Jennings, 2019)
Tracheal chondrocytes arise from the splanchnic foregut mesoderm In order to investigate the mechanisms of early tracheal chondrogenesis, we first performed lineage-tracing experiments to confirm that the Sox9+ tracheal chondrocytes are derived from the lateral plate mesoderm and not the neural crest, which give rise to laryngeal cartilage (Tabler et al, 2017)
In this study, we show that conditional mouse mutants with relatively high levels of GliR, mimicking Pallister–Hall Syndrome (PHS), exhibit tracheomalacia and fail to properly specify Sox9+ tracheal chondrocytes
Summary
Impaired formation of the tracheal cartilage, or tracheomalacia, occurs in 1 in 2100 live births and can result in life-threatening airway collapse and impaired breathing (Boogaard et al, 2005; Kamran and Jennings, 2019). Generating biologically accurate replacement tissue from pluripotent stem cells is an aspirational strategy to improve patient care, but this requires a detailed understanding of both normal fetal tracheal development and the etiology of tracheomalacia (Fraga et al, 2016; Wallis et al, 2019). Tracheal cartilage development in the mouse begins by embryonic day (E)11.5 with expression of the transcription factor Sox, a master regulator of chondrogenesis, in the ventral and lateral splanchnic mesenchyme surrounding the fetal trachea (Hines et al, 2013). Hedgehog (HH) and Wnt signaling are critical for tracheal cartilage development in mice, and mutations in these pathways have been associated with tracheomalacia in patients; how these pathways interact to regulate tracheal chondrogenesis is unclear (Sinner et al, 2019)
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