A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease

Soret, Rodolphe; Mennetrey, Mathilde; Bergeron, Karl-F.; Dariel, Anne; Neunlist, Michel; Grunder, Franziska; Fauré, Christophe; Silversides, David W.; Pilon, Nicolas

doi:10.1172/jci83178

Cited by 85 publications

(109 citation statements)

References 71 publications

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“…Soret and colleagues identified a new mechanism that causes HSCR-like disease in mice and involves deposition of excess collagen VI in the intestine by migrating ENS precursors as they colonize the fetal bowel (Soret et al, 2015). The description of a new mouse model, named Holstein , which was generated through an insertional mutagenesis screen that led to altered gene expression of the collagen-6α4 ( Col6a4 ) gene is described further in the section entitled “Beyond genes: role of regulatory sequences, miRNAs and environmental factors”.…”

Section: Molecular Mediators That Control Ens Development and Maturatmentioning

confidence: 99%

Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players

Bondurand

Southard‐Smith

2016

Developmental Biology

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Hirschsprung disease (HSCR, intestinal aganglionosis) is a multigenic disorder with variable penetrance and severity that has a general population incidence of 1/5000 live births. Studies using animal models have contributed to our understanding of the developmental origins of HSCR and the genetic complexity of this disease. This review summarizes recent progress in understanding control of enteric nervous system (ENS) development through analyses in mouse models. An overview of signaling pathways that have long been known to control the migration, proliferation and differentiation of enteric neural progenitors into and along the developing gut is provided as a framework for the latest information on factors that influence enteric ganglia formation and maintenance. Newly identified genes and additional factors beyond discrete genes that contribute to ENS pathology including regulatory sequences, miRNAs and environmental factors are also introduced. Finally, because HSCR has become a paradigm for complex oligogenic diseases with non-Mendelian inheritance, the importance of gene interactions, modifier genes, and initial studies on genetic background effects are outlined.

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Section: Molecular Mediators That Control Ens Development and Maturatmentioning

confidence: 99%

Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players

Bondurand

Southard‐Smith

2016

Developmental Biology

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“…In this issue, Soret and colleagues took an unbiased, forward genetics approach and used insertional mutagenesis to identify potential regulators of neural crest-derived cell (NCC) migration (22). To simplify the screening process, Soret et al randomly inserted a tyrosinase (Tyr) minigene, which rescues pigment production in NCCderived melanocytes, into albino FVB/N mice and then evaluated animals with nonuniform pigment patterns.…”

Section: Unbiased Approach To Identify Genes Critical For Ens Developmentioning

confidence: 99%

“…Interactions between ENCDCs and the extracellular matrix along the migratory route also influence ENCDC behavior. In this issue, Soret and colleagues demonstrate that animals with excess collagen VI develop HSCR-like disease due to decreased ENCDC migration (22). Moreover, the inhibitory effect of collagen VI on ENCDC migration may partially explain why children with Down syndrome have an increased risk of HSCR, since collagen VI genes are on chromosome 21.…”

Section: Unbiased Approach To Identify Genes Critical For Ens Developmentioning

confidence: 99%

“…These collagen genes are expressed in ENCDCs and overexpressed in the skin of human fetuses with trisomy 21, in which they probably exclusively interact with COL6A3 to form classical α1-α2-α3 trimeric collagen monomers. Soret and colleagues analyzed human colon muscle with myenteric ganglia from a cohort of patients with HSCR and healthy controls to test their hypothesis that excess collagen VI might increase human HSCR risk (22). Remarkably, collagen VI was more abundant in tissue surrounding myenteric ganglia of children with HSCR compared with that in control specimens (2-fold higher) and present at even higher levels surrounding myenteric ganglia of children with Down syndrome and HSCR (3-fold higher).…”

Section: Unbiased Approach To Identify Genes Critical For Ens Developmentioning

confidence: 99%

“…Soret et al next hypothesized that their observations in mice may be relevant for human HSCR and could explain the increased HSCR occurrence in children with Down syndrome (22). The translation…”

Section: Increased Collagen VI Links Hscr and Down Syndromementioning

confidence: 99%

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Hirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migration

Heuckeroth¹

2015

Journal of Clinical Investigation

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C o m m e n t a r y4 3 (17), suggesting that one or more genes on chromosome 21 contributes to HSCR etiology. Up to 10% of children with HSCR have Down syndrome, and 1% to 2% of children with Down syndrome have HSCR. Thus, Down syndrome increases HSCR risk about 50-to 100-fold above the general population risk (~1:5,000) and is a common underlying partially penetrant cause of HSCR (4).Over the past few decades there have been dramatic advances in our understanding of HSCR anatomy, embryology, physiology, and genetics (4,5,18). Early studies by Yntema and Hammond showed that the ENS forms from enteric neural crestderived cells (ENCDCs) that originate primarily in the vagal region of the neural tube (19). These ENCDCs proliferate vigorously as they colonize fetal bowel in a rostral to caudal progression, pursuing one of the longest migratory routes of any cell population during fetal development ( Figure 1A). ENCDCs then differentiate into diverse neuron and glia subtypes that form a network in the bowel wall with about as many neurons as the spinal cord and every transmitter in the central nervous system (3, 18). Despite these advances in our understanding of ENS development, the causal link between trisomy 21 and increased HSCR incidence has remained elusive. Analysis of partial trisomy 21 phenotypes suggested that an extra copy of at least one gene in the interval from 33.5 to 46.25 Mb increased HSCR risk (20). This interval contains 122 known genes, including DSCAM, BACE2, COL18A1, and COL6A1. A recent SNP association study suggested that excess DSCAM may be important for HSCR pathogenesis in Down syndrome, but excess DSCAM has not been confirmed experimentally to cause HSCR-like disease in model systems (21). Unbiased approach to identify genes critical for ENS developmentIn this issue, Soret and colleagues took an unbiased, forward genetics approach and used insertional mutagenesis to identify potential regulators of neural crest-derived cell (NCC) migration (22). To simplify the screening process, Soret et al. randomly inserted a tyrosinase (Tyr) minigene, which rescues pigment production in NCCderived melanocytes, into albino FVB/N mice and then evaluated animals with nonuniform pigment patterns. Because melanocytes and the ENS are both neural crest derivatives, some mice with pigmentation defects were also expected to have ENS defects, mimicking the human "neurocristopathy" called Waardenburg-Shah syndrome (Waardenburg syndrome type Hirschsprung's disease (HSCR) causes functional intestinal obstruction due to the absence of the enteric nervous system (ENS) in the distal bowel and is usually diagnosed shortly after birth or during childhood. While several genetic and nongenetic factors have been linked to HSCR, the underlying mechanisms that prevent ENS precursors from colonizing distal bowel during fetal development are not completely understood in many affected children. In this issue of the JCI, Soret and colleagues identify a new mechanism that causes HSCR-like disease in mice and involves deposition o...

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Intestinal fibrosis in aganglionic segment of Hirschsprung's disease revealed by single‐cell RNA sequencing

Wang

Huang

et al. 2023

Clinical & Translational Med

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Background Hirschsprung's disease (HSCR) is a relatively common congenital disability. Accumulating extracellular matrix (ECM) prompts intestinal fibrosis remodelling in the aganglionic segments of HSCR. The contributions of various cellular subsets in the fibrogenesis of HSCR segments are poorly understood. Methods Single‐cell transcriptomics from 8 aganglionic segments and 5 normal segments of 7 HSCR subjects and 26 healthy segments of seven healthy donors were analysed. Fibrotic phenotype and alterations were explored using differential expression analysis and single‐cell trajectory analysis. Fibrosis‐related transcription factors were inferred through single‐cell regulatory network inference. Bulk transcriptomic data, proteomic data, immunohistochemistry (IHC) and real‐time polymerase chain reaction were used to validate the alterations in the HSCR intestine. Results Various collagen, fibronectin and laminin protein‐coding genes expression were up‐regulated in the stromal and glial cells of the HSCR intestine. The number of fibroblasts and myofibroblasts in the aganglionic segments increased, and more myofibroblasts were activated at an earlier stage in HSCR segments, which infers that there is an intestinal fibrosis phenotype in HSCR segments. The fibrotic regulators POSTN , ANXA1 and HSP70 were highly expressed in the ECM‐related cellular subsets in the transitional segments and aganglionic segments. The transcription factor regulatory network revealed that fibrosis‐related and megacolon‐related NR2F1 in the fibroblasts and glial subsets was up‐regulated in the aganglionic segment. Conclusions This work identifies intestinal fibrosis and related regulators in aganglionic segments of HSCR; hence, anti‐fibrotic therapy may be considered to prevent HSCR‐associated enterocolitis (HAEC), relieve intestinal stricture and improve cell therapy.

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A collagen VI–dependent pathogenic mechanism for Hirschsprung’s disease

Cited by 85 publications

References 71 publications

Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players

Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players

Hirschsprung’s disease, Down syndrome, and missing heritability: too much collagen slows migration

Intestinal fibrosis in aganglionic segment of Hirschsprung's disease revealed by single‐cell RNA sequencing

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