Sfrp Controls Apicobasal Polarity and Oriented Cell Division in Developing Gut Epithelium

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.

导致器官形态改变的上皮管状形态发生（epithelial tubular morphogenesis）具有重要的生理意义。然而，目前对于调控上皮管状形态发生的分子机制仍知之甚少。本研究发现，分泌型卷曲相关蛋白1（Sfrp1）与分泌型卷曲相关蛋白2（Sfrp2）的功能缺失会导致小鼠胚胎前胃（fore-stomach）长度缩短，且该表型在同时携带Sfrp5突变时会进一步增强。在正常状态下，前胃上皮的单细胞层中，细胞分裂通常沿头尾轴（cephalocaudal axis）定向进行；而在Sfrps缺陷的前胃中，细胞分裂方向出现紊乱。Sfrps缺陷的前胃上皮中，细胞增殖与凋亡并未受到影响。类似地，当Frizzled/平面细胞极性（Fz/PCP）通路组分Stbm/Vangl2或Wnt5a功能失活时，前胃上皮的细胞分裂方向同样会出现异常。上述结果表明，由Frizzled/平面细胞极性（Fz/PCP）通路调控的定向细胞分裂，是前胃形态发生过程中的关键调控环节之一。此外，Sfrps复合突变小鼠的小肠上皮无法维持正常的顶基极性（apicobasal polarity），该缺陷同样在Wnt5a功能失活的小肠组织中被观察到。结合上述发现，Sfrp1可与Wnt5a发生物理性相互作用，并抑制Wnt5a信号通路。我们提出，Sfrps通过调控Wnt5a信号通路，控制发育过程中肠道上皮的定向细胞分裂与顶基极性。