Villification in the mouse: Bmp signals control intestinal villus patterning

Abstract

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.

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

“…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).…”

“…Although, in both, looping results from differential growth between the gut tube and mesentery, the degree of differential growth is twofold higher in the chick than the finch (1). Because bone morphogenetic proteins (BMPs) have been strongly implicated in other aspects of gut and mesentery organogenesis (13)(14)(15)(16)(17)(18), we compared BMP signaling in the embryonic chick and finch dorsal mesentery by immunofluorescent detection of phosphorylated Smad 1/5/8. In the chick, phosphoSmad levels temporally correlated with the progression of looping morphogenesis ( Fig.…”

Generation of intestinal surface: an absorbing tale

“…Pseudostratification allows efficient packing of a large number of tall, thin, rapidly dividing cells in a relatively restricted space (Lee and Norden, 2013). As villi begin to emerge, cells at the tips of the outgrowing villi shorten and widen (Walton et al, 2016), expanding the apical surface area of the intestinal tube substantially. Such shape changes might also drive lengthening of the gut tube (Fig.…”

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

“…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.…”

“…Meanwhile, villus cells are postmitotic and express genes appropriate to their differentiated function in secretion or absorption; epithelial cells transit towards the villus tips, where they ultimately delaminate into the lumen. A number of developmental signaling molecules and transcriptional regulators have been implicated in villus development (Choi et al, 2006;Kaestner et al, 1997;Karlsson et al, 2000;Kim et al, 2007;Lepourcelet et al, 2005;Madison et al, 2005;McLin et al, 2009;Ormestad et al, 2006;Shyer et al, 2013;Spence et al, 2011;van den Brink, 2007;Walker et al, 2014;Walton et al, 2012Walton et al, , 2016; however, the role of metabolic regulators in villus development has yet to be investigated.…”