Loss of sonic hedgehog gene leads to muscle development disorder and megaesophagus in mice

Jia, Xueting; Min, Li; Zhu, Shengtao; Zhang, Shutian; Huang, Xiaofeng

doi:10.1096/fj.201701581r

Cited by 6 publications

(6 citation statements)

References 44 publications

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“…Second, esophagus muscularis was associated with the lung trait FEV1/FVC 44 ( π t ′ = 0.15, s.e. = 0.053, P = 1.7 × 10 −3 ), consistent with previous work reporting that acidification of the esophagus leads to airway constriction 45 and birth defects in the esophagus have consequences for pulmonary function likely stemming from shared causal mechanisms in Sonic hedgehog 46-49 . FEV1/FVC is computed by dividing the amount of air an individual can expel from their lungs in one second (FEV1) by total lung capacity (FVC); therefore, the esophagus muscularis could impact either FEV1 and/or FVC.…”

Section: Resultssupporting

confidence: 89%

Modeling tissue co-regulation to estimate tissue-specific contributions to disease

Amariuta

Siewert

Price

2022

Preprint

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Integrative analyses of genome-wide association studies (GWAS) and gene expression data across diverse tissues and cell types have enabled the identification of putative disease-critical tissues. However, co-regulation of genetic effects on gene expression across tissues makes it difficult to distinguish biologically causal tissues from tagging tissues. While previous work emphasized the potential of accounting for tissue co-regulation, tissue-specific disease effects have not previously been formally modeled. Here, we introduce a new method, tissue co-regulation score regression (TCSC), that disentangles causal tissues from tagging tissues and partitions disease heritability (or covariance) into tissue-specific components. TCSC leverages gene-disease association statistics across tissues from transcriptome-wide association studies (TWAS), which implicate both causal and tagging genes and tissues. TCSC regresses TWAS chi-square statistics (or products of z-scores) on tissue co-regulation scores reflecting correlations of predicted gene expression across genes and tissues. In simulations, TCSC powerfully distinguishes causal tissues from tagging tissues while controlling type I error. We applied TCSC to GWAS summary statistics for 78 diseases and complex traits (average N = 302K) and gene expression prediction models for 48 GTEx tissues. TCSC identified 27 causal tissue-trait pairs at 10% FDR, including well-established findings, biologically plausible novel findings (e.g. aorta artery and glaucoma), and increased specificity of known tissue-trait associations (e.g. subcutaneous adipose, but not visceral adipose, and HDL). TCSC also identified 30 causal tissue-trait covariance pairs at 10% FDR. For the positive genetic covariance between eosinophil count and white blood cell count, whole blood contributed positive covariance while LCLs contributed negative covariance; this suggests that genetic covariance may reflect distinct tissue-specific contributions. Overall, TCSC is a powerful method for distinguishing causal tissues from tagging tissues, improving our understanding of disease and complex trait biology.

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Section: Resultssupporting

confidence: 89%

Modeling tissue co-regulation to estimate tissue-specific contributions to disease

Amariuta

Siewert

Price

2022

Preprint

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“…All mutants also showed varying losses of the dorsal trachealis muscle ( Figure 1B) as well as some degrees of esophageal stenosis, supporting that HH/Gli signaling is also required for esophageal development (Jia et al, 2018;Litingtung et al, 1998).…”

Section: Hh/gli Imbalance Leads To Tracheomalaciamentioning

confidence: 61%

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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“…At a minimum, biological triplicates were analyzed. The organ culture system was described previously ( Jia et al., 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…Sections were prepared as previously reported ( Jia et al., 2018 ). Antibodies against the following were used for immunohistochemical analysis: proliferating cell nuclear antigen (PCNA, mouse or rabbit monoclonal; 1:50, Santa Cruz Biotechnology), Claudin 1 (CLDN1, Proteintech), Claudin 4 (CLDN4, Proteintech), SHH (1:50, Abcam), GLI1 (1:50, Abcam).…”

Section: Methodsmentioning

confidence: 99%

Porphyromonas gingivalis secretion leads to dysplasia of normal esophageal epithelial cells via the Sonic hedgehog pathway

Jia

Liu

et al. 2022

Front. Cell. Infect. Microbiol.

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ObjectivesTo investigate the pathogenic effect of Porphyromonas gingivalis cultured media on the esophagus and the mechanism underlying the effect.BackgroundPeriodontitis is strongly associated with esophageal squamous cell carcinoma (ESCC). The cultured media of P. gingivalis may act on healthy esophagus to trigger a malignant transformation; however, this has not been confirmed.MethodsCell migration assays and cell cycle measurements were performed on normal human esophageal epithelial cells in the presence or absence of P. gingivalis cultured media. The esophagi of healthy adult C57BL/6J mice were isolated and cultured in-vitro. Hematoxylin-eosin and immunohistochemical staining using antibodies against proliferating cell nuclear antigen (PCNA), Claudin 1 and Claudin 4 were performed to detect dysplasia in specific tissues. Total mRNA was extracted to determine transcriptional dysregulation. A specific inhibitor of Sonic hedgehog signaling, cyclopamine, was used to confirm the underlying molecular mechanism.ResultsIn the presence of P. gingivalis cultured media, proliferation and migration of normal human esophageal epithelial cells were up-regulated, and aneuploid cells appeared. Compared with control cells, the arrangement of mouse esophageal epithelial cells became disordered, the percentage of PCNA-positive cells increased, and the positive staining of Claudin 1 and Claudin 4 became weak. In addition, the expression of cancer-related pathway genes was up-regulated but tight junction-related gene expression was down-regulated. The Sonic hedgehog pathway was abnormally activated, and its inhibition reduced the pathogenic effect of P. gingivalis cultured media.ConclusionsWe revealed that the cultured media of the key periodontal pathogen, P. gingivalis, can induce the malignant transformation of normal esophageal epithelium through the Sonic hedgehog pathway.

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Loss of sonic hedgehog gene leads to muscle development disorder and megaesophagus in mice

Cited by 6 publications

References 44 publications

Modeling tissue co-regulation to estimate tissue-specific contributions to disease

Modeling tissue co-regulation to estimate tissue-specific contributions to disease

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

Porphyromonas gingivalis secretion leads to dysplasia of normal esophageal epithelial cells via the Sonic hedgehog pathway

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