Complete Tracheal Ring Deformity. A Translational Genomics Approach to Pathogenesis

Sinner, Débora; Carey, Brenna; Zgherea, Daniela; Kaufman, Kenneth M.; Leesman, Lauren; Wood, Robert E.; Rutter, Michael J.; Alarcón, Alessandro de; Elluru, Ravindhra G.; Harley, John B.; Whitsett, Jeffrey A.; Trapnell, Bruce C.

doi:10.1164/rccm.201809-1626oc

Cited by 30 publications

(40 citation statements)

References 65 publications

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“…We next intersected the Gli3R-regulated transcripts with a manually curated list of 61 genes implicated in tracheal chondrogenesis and/or tracheomalacia in mice or humans (Supplemental Table 2). These were identified from a review of the literature (Sinner et al, 2019) (Supplemental Figure 3C) and by searching the Monarchinitiative.org, an online knowledgebase that aggregates human disease and animal model genotype-phenotypes associations (Shefchek et al, 2020). This intersection revealed five genes, all of which were downregulated in Gli3T transgenic embryos ( Figure 5C), consistent with them being direct targets of Gli3 repressor activity.…”

Section: Tracheal Chondrogenesismentioning

confidence: 94%

“…Foxg1Gli3T Flag/+ tracheas as determined by Log2FC >|1|, p<0.05. C: Venn diagram intersecting genes differentially expressed in Foxg1Cre;Gli3T Flag/+ mutants with genes known to be involved in human and mouse tracheal chondrogenesis (Shefchek et al, 2020;Sinner et al, 2019). TM = tracheomalaciaassociated genes.…”

Section: Rna-seq and Chip-seq Analysismentioning

confidence: 99%

“…By E15.5, the chondrocytes differentiate into cartilage rings (Park et al, 2010). 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, but how these pathways interact to regulate tracheal chondrogenesis is unclear (Sinner et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Disruption of a Hedgehog-Foxf1-Rspo2 Signaling Axis Leads to Tracheomalacia and a Loss of Sox9+ Tracheal Chondrocytes

Nasr

Chaturvedi

Agarwal

et al. 2020

Preprint

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Congenital 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 a HH-Foxf1-Rspo2 signaling axis that governs tracheal cartilage development and informs the etiology of tracheomalacia.SUMMARY STATEMENTThis work provides a mechanistic basis for tracheomalacia in patients with Hedgehog pathway mutations.

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Section: Tracheal Chondrogenesismentioning

confidence: 94%

Section: Rna-seq and Chip-seq Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disruption of a Hedgehog-Foxf1-Rspo2 Signaling Axis Leads to Tracheomalacia and a Loss of Sox9+ Tracheal Chondrocytes

Nasr

Chaturvedi

Agarwal

et al. 2020

Preprint

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“…Tracheal rings (TR) are rare, congenital cartilaginous defect of the upper airway and are usually due to complete or near complete circumferential cartilaginous tracheal rings, with variable degrees of tracheal stenosis (TS) and shortening [1]. In the normal trachea, the cartilaginous rings are C-shaped but if the tracheal rings grow out of proportion to the posterior membranous trachea, there is restricted tracheal growth leading to TS [1,2]. In the more severe forms of TS, as in cases of complete tracheal rings (CTR), absence of tracheal pars membranacea creates an hourglass trachea [3].…”

Section: Introductionmentioning

confidence: 99%

Tracheal Stenosis and Congenital Heart Disease in Trisomy 21

Kylat

2019

Children

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Tracheal rings (TR) are rare, congenital cartilaginous defect of the upper airway and are usually due to complete or near complete circumferential cartilaginous tracheal rings, with variable degrees of tracheal stenosis (TS) and shortening. Chromosomal anomalies like trisomy 21 are characteristically associated with a wide range of upper airway anomalies including TS and congenital heart disease (CHD). However, the overall prevalence of severe forms of TS is rare and reported in 1.2% of all CHD patients. Herein, we present a rare association of severe TS due to complete tracheal rings in a trisomy 21 patient with CHD and the challenges in the management.

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“…In this issue of the Journal , Sinner and colleagues (pp. 1267–1281) uncover multiple human genetic lesions that lead to CTRD, including mutations in genes within the SHH pathway and mutations in multiple genes within the WNT pathway, including ROR2 (receptor tyrosine kinase–like orphan receptor 2) (7) (Figure 1). This study highlights the close relationship between mouse models of respiratory development and human congenital tracheal abnormalities, and it provides new target genes and pathways that play an important role in tracheal development in humans.…”

mentioning

confidence: 99%