Bending Gradients: How the Intestinal Stem Cell Gets Its Home

Shyer, Amy E.; Huycke, Tyler R.; Lee, ChangHee; Mahadevan, L.; Tabin, Clifford J.

doi:10.1016/j.cell.2015.03.041

Cited by 250 publications

(320 citation statements)

References 41 publications

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“…Although recent work has identified developmental signals involved in villus formation (15,22,23), the molecular mechanisms underlying looping of the intestine have remained largely unknown. On the other hand, the physics of intestinal looping has been well characterized (1).…”

Section: Discussionmentioning

confidence: 99%

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

Nerurkar

Mahadevan

Tabin

2017

Proc. Natl. Acad. Sci. U.S.A.

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Looping of the initially straight embryonic gut tube is an essential aspect of intestinal morphogenesis, permitting proper placement of the lengthy small intestine within the confines of the body cavity. The formation of intestinal loops is highly stereotyped within a given species and results from differential-growth–driven mechanical buckling of the gut tube as it elongates against the constraint of a thin, elastic membranous tissue, the dorsal mesentery. Although the physics of this process has been studied, the underlying biology has not. Here, we show that BMP signaling plays a critical role in looping morphogenesis of the avian small intestine. We first exploited differences between chicken and zebra finch gut morphology to identify the BMP pathway as a promising candidate to regulate differential growth in the gut. Next, focusing on the developing chick small intestine, we determined that Bmp2 expressed in the dorsal mesentery establishes differential elongation rates between the gut tube and mesentery, thereby regulating the compressive forces that buckle the gut tube into loops. Consequently, the number and tightness of loops in the chick small intestine can be increased or decreased directly by modulation of BMP activity in the small intestine. In addition to providing insight into the molecular mechanisms underlying intestinal development, our findings provide an example of how biochemical signals act on tissue-level mechanics to drive organogenesis, and suggest a possible mechanism by which they can be modulated to achieve distinct morphologies through evolution.

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Section: Discussionmentioning

confidence: 99%

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

Nerurkar

Mahadevan

Tabin

2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In that model, the initially flat epithelium gives way to longitudinal ridges, which evolve to regular zigzags and finally to villi, and these sequential morphological stages correlate with maturation of three smooth muscle layers (Coulombre and Coulombre, 1958;Shyer et al, 2013). The deep and regular folding of the epithelium, imposed by mechanical forces from the developing muscles, creates periodic maxima of epithelially secreted Hedgehog (Hh) protein beneath the folded epithelium that direct villus emergence in a regular manner (Shyer et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Villification in the mouse: Bmp signals control intestinal villus patterning

et al. 2015

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In the intestine, finger-like villi provide abundant surface area for nutrient absorption. During murine villus development, epithelial Hedgehog (Hh) signals promote aggregation of subepithelial mesenchymal clusters that drive villus emergence. Clusters arise first dorsally and proximally and spread over the entire intestine within 24 h, but the mechanism driving this pattern in the murine intestine is unknown. In chick, the driver of cluster pattern is tensile force from developing smooth muscle, which generates deep longitudinal epithelial folds that locally concentrate the Hh signal, promoting localized expression of cluster genes. By contrast, we show that in mouse, muscle-induced epithelial folding does not occur and artificial deformation of the epithelium does not determine the pattern of clusters or villi. In intestinal explants, modulation of Bmp signaling alters the spatial distribution of clusters and changes the pattern of emerging villi. Increasing Bmp signaling abolishes cluster formation, whereas inhibiting Bmp signaling leads to merged clusters. These dynamic changes in cluster pattern are faithfully simulated by a mathematical model of a Turing field in which an inhibitor of Bmp signaling acts as the Turing activator. In vivo, genetic interruption of Bmp signal reception in either epithelium or mesenchyme reveals that Bmp signaling in Hh-responsive mesenchymal cells controls cluster pattern. Thus, unlike in chick, the murine villus patterning system is independent of muscle-induced epithelial deformation. Rather, a complex cocktail of Bmps and Bmp signal modulators secreted from mesenchymal clusters determines the pattern of villi in a manner that mimics the spread of a self-organizing Turing field.

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“…Over the next 6 days of development, proliferation in the epithelium accompanies a tremendous expansion in the length and circumference of the intestine. By E14.5-E16.5, condensations of mesenchymal cells arise and serve as signaling centers that trigger the overlying epithelium to withdraw from the cell cycle, undergo a transition to a simple columnar morphology, and extend into luminal projections called villi (Burns et al, 2004;Kaestner et al, 1997;Madison et al, 2009;Mathan et al, 1976;Noah et al, 2011;Pabst et al, 1997Pabst et al, , 1999Shyer et al, 2015;Walton et al, 2012Walton et al, , 2016. Cells between villi remain proliferative and will ultimately undergo a morphological restructuring to form crypts of Lieberkhün.…”

Section: Introductionmentioning

confidence: 99%

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

et al. 2016

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During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders.

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Bending Gradients: How the Intestinal Stem Cell Gets Its Home

Cited by 250 publications

References 41 publications

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

BMP signaling controls buckling forces to modulate looping morphogenesis of the gut

Villification in the mouse: Bmp signals control intestinal villus patterning

A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis

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