Epithelial tubular morphogenesis leading to alteration of organ shape has important physiological consequences. However, little is known regarding the mechanisms that govern epithelial tube morphogenesis. Here, we show that inactivation of Sfrp1 and Sfrp2 leads to reduction in fore-stomach length in mouse embryos, which is enhanced in the presence of the Sfrp5 mutation. In the mono-cell layer of fore-stomach epithelium, cell division is normally oriented along the cephalocaudal axis; in contrast, orientation diverges in the Sfrps-deficient fore-stomach. Cell growth and apoptosis are not affected in the Sfrps-deficient fore-stomach epithelium. Similarly, cell division orientation in fore-stomach epithelium diverges as a result of inactivation of either Stbm/Vangl2, an Fz/PCP component, or Wnt5a. These observations indicate that the oriented cell division, which is controlled by the Fz/PCP pathway, is one of essential components in fore-stomach morphogenesis. Additionally, the small intestine epithelium of Sfrps compound mutants fails to maintain proper apicobasal polarity; the defect was also observed in Wnt5a-inactivated small intestine. In relation to these findings, Sfrp1 physically interacts with Wnt5a and inhibits Wnt5a signaling. We propose that Sfrp regulation of Wnt5a signaling controls oriented cell division and apicobasal polarity in the epithelium of developing gut.
The gastrointestinal tract is generated from the primitive gut tube during embryogenesis. The primitive gut differentiates regionally along the cephalocaudal axis. Individual regions simultaneously acquire specific morphologies through morphogenetic mechanisms. The regional specification of the gut tube is controlled by cross-talk between the mesenchyme and epithelium. However, the morphogenetic mechanisms governing gut formation remain poorly understood. Secreted Frizzled-related protein (Sfrp) is an inhibitor of the Wnt pathway, members of which are expressed in the developing gut. A deficiency of Sfrp genes (Sfrp1, Sfrp2, and Sfrp5) results in reduction of fore-stomach length in mice. During normal fore-stomach formation, cell division is oriented along the cephalocaudal axis; in contrast, reduced fore-stomach length in Sfrps-deficient mice is associated with the divergence of oriented cell division in tubular epithelial cells. Thus, oriented cell division is one of the essential components in fore-stomach morphogenesis. In addition, Sfrps-deficient small intestine epithelium fails to maintain proper apicobasal polarity. We also found that Wnt5a-inactivation leads to a phenotype similar to that induced by Sfrps-deficiency in the developing gut, and that Sfrp1 inhibits Wnt5a signaling. We propose that Sfrp regulation of Wnt5a signaling is required for oriented cell division and that it modulates apicobasal polarity in gut epithelium during organ elongation.