Molecular etiology of gut malformations and diseases

Barbara, Pascal de Santa; Brink, Gijs R. van den; Roberts, Drucilla J.

doi:10.1002/ajmg.10978

Cited by 63 publications

(36 citation statements)

References 108 publications

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“…Thus, we cannot exclude the possibility that Jag1 staining at the basal membrane of crypt cells is of mesenchymal origin. This assumption reinforces the model in which complex cellcell, including epithelial-mesenchymal, interactions play a pivotal role in gut development and homeostasis (reviewed by Kedinger et al, 1998;De Santa Barbara et al, 2002;Faure and de Santa Barbara, 2011).…”

Section: Discussionsupporting

confidence: 74%

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

et al. 2015

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Thyroid hormones control various aspects of gut development and homeostasis. The best-known example is in gastrointestinal tract remodeling during amphibian metamorphosis. It is well documented that these hormones act via the TR nuclear receptors, which are hormone-modulated transcription factors. Several studies have shown that thyroid hormones regulate the expression of several genes in the Notch signaling pathway, indicating a possible means by which they participate in the control of gut physiology. However, the mechanisms and biological significance of this control have remained unexplored. Using multiple in vivo and in vitro approaches, we show that thyroid hormones positively regulate Notch activity through the TRα1 receptor. From a molecular point of view, TRα1 indirectly controls Notch1, Dll1, Dll4 and Hes1 expression but acts as a direct transcriptional regulator of the Jag1 gene by binding to a responsive element in the Jag1 promoter. Our findings show that the TRα1 nuclear receptor plays a key role in intestinal crypt progenitor/stem cell biology by controlling the Notch pathway and hence the balance between cell proliferation and cell differentiation.

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Section: Discussionsupporting

confidence: 74%

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

et al. 2015

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“…Hh ligands (Shh and Ihh), which are expressed in the epithelium from early developmental stages, signal in a paracrine fashion to the mesenchyme (Kolterud et al, 2009;Ramalho-Santos et al, 2000). Loss of both Hh ligands or deletion of the major Hh signal transducer, smoothened (Smo), severely reduces mesenchymal proliferation and results in a digestive tract that is 90% shorter than controls -even shorter than the Wnt5a −/− gut (de Santa Barbara et al, 2002;Mao et al, 2010). Similarly, inactivating Notch signaling by deletion of the Notch effector Rbpj only in the mesenchyme diminishes the number of subepithelial fibroblasts and results in intestines that are 20-30% shorter than controls .…”

Section: Ror2mentioning

confidence: 99%

Generation of intestinal surface: an absorbing tale

et al. 2016

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The vertebrate small intestine requires an enormous surface area to effectively absorb nutrients from food. Morphological adaptations required to establish this extensive surface include generation of an extremely long tube and convolution of the absorptive surface of the tube into villi and microvilli. In this Review, we discuss recent findings regarding the morphogenetic and molecular processes required for intestinal tube elongation and surface convolution, examine shared and unique aspects of these processes in different species, relate these processes to known human maladies that compromise absorptive function and highlight important questions for future research.

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“…In addition, the splanchnic mesoderm-derived mesenchyme that underlies the gut is organized along a radial axis of symmetry into distinct cell layers establishing oriented smooth muscle bands that control local movement of the gut tube. Organogenesis and tissue homeostasis within the digestive tract require continuous interaction between endodermal epithelium and subjacent mesenchyme (Haffen et al, 1987;Kedinger et al, 1998), and disruption of these interactions is implicated in human gastrointestinal (GI) birth defects and cancers (Bhowmick et al, 2004;de Santa Barbara et al, 2002;Yauch et al, 2008). Despite their importance, the molecular mediators of epithelial-mesenchymal interchange are poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

“…In a chicken GI explant culture, Shh was shown to regulate mesenchymal patterning and inhibit smooth muscle differentiation (Sukegawa et al, 2000). Proliferation of intestinal intervillus epithelium is reduced in Ihh -/-mice (Ramalho-Santos et al, 2000), whereas Shh -/-mice show multiple gut anomalies, including tracheo-esophageal fistula and anorectal atresia (Litingtung et al, 1998;Ramalho-Santos et al, 2000), among the common congenital GI anomalies observed in humans with mutations in Hh pathway genes (Arsic et al, 2002;de Santa Barbara et al, 2002;Kang et al, 1997;Kim et al, 2001;Nanni et al, 1999). However, the modest phenotypes of individual Shh or Ihh mutants and the extensive overlap in their expression domains are indicative of a potential redundancy in their actions, a conclusion supported by the enhancing action of reducing gene dosage in a background sensitized by the loss of one these proteins (RamalhoSantos et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract

et al. 2010

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Homeostasis of the vertebrate digestive tract requires interactions between an endodermal epithelium and mesenchymal cells derived from the splanchnic mesoderm. Signaling between these two tissue layers is also crucial for patterning and growth of the developing gut. From early developmental stages, sonic hedgehog (Shh) and indian hedgehog (Ihh) are secreted by the endoderm of the mammalian gut, indicative of a developmental role. Further, misregulated hedgehog (Hh) signaling is implicated in both congenital defects and cancers arising from the gastrointestinal tract. In the mouse, only limited gastrointestinal anomalies arise following removal of either Shh or Ihh. However, given the considerable overlap in their endodermal expression domains, a functional redundancy between these signals might mask a more extensive role for Hh signaling in development of the mammalian gut. To address this possibility, we adopted a conditional approach to remove both Shh and Ihh functions from early mouse gut endoderm. Analysis of compound mutants indicates that continuous Hh signaling is dispensable for regional patterning of the gut tube, but is essential for growth of the underlying mesenchyme. Additional in vitro analysis, together with genetic gain-of-function studies, further demonstrate that Hh proteins act as paracrine mitogens to promote the expansion of adjacent mesenchymal progenitors, including those of the smooth muscle compartment. Together, these studies provide new insights into tissue interactions underlying mammalian gastrointestinal organogenesis and disease.

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Molecular etiology of gut malformations and diseases

Cited by 63 publications

References 108 publications

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine

Generation of intestinal surface: an absorbing tale

Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract

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