Sfrp controls apicobasal polarity and oriented cell division in developing gut epithelium.
Sfrp controls apicobasal polarity and oriented cell division in developing gut epithelium.
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DOI：
10.1371/journal.pgen.1000427
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发表时间：
2009-03
期刊：
影响因子：
4.5
通讯作者：
Shimono A
中科院分区：
文献类型：
--
作者：
Matsuyama M;Aizawa S;Shimono A
上皮管状形态发生导致器官形状的改变具有重要的生理后果。然而，很少有人知道关于上皮管形态发生的机制。在这里，我们表明，Sfrp 1和Sfrp 2的失活导致小鼠胚胎前胃长度的减少，这是在Sfrp 5突变的存在下增强。在前胃上皮的单细胞层中，细胞分裂通常沿沿着头尾轴定向;相反，在Sfrps缺陷的前胃中定向发散。Sfrps缺陷的前胃上皮细胞的生长和凋亡不受影响。类似地，由于Stbm/Vangl 2、Fz/PCP组分或Wnt 5a的失活，前胃上皮中的细胞分裂方向发散。这些观察结果表明，由Fz/PCP途径控制的定向细胞分裂是前胃形态发生的重要组成部分之一。此外，Sfrps复合突变体的小肠上皮不能保持适当的顶基极性;在Wnt 5a失活的小肠中也观察到缺陷。与这些发现相关，Sfrp 1与Wnt 5a物理相互作用并抑制Wnt 5a信号传导。我们提出，Sfrp调控Wnt 5a信号控制定向细胞分裂和apicobasal极性在上皮细胞的发展肠道。胃肠道在胚胎发生过程中由原肠管产生。原肠沿着头尾轴区域性分化。个别地区同时获得特定的形态通过形态发生机制。肠管的区域规格由间充质和上皮之间的串扰控制。然而，肠道形成的形态发生机制仍然知之甚少。分泌型卷曲相关蛋白（Sfrp）是Wnt通路的抑制剂，其成员在发育中的肠道中表达。Sfrp基因（Sfrp 1，Sfrp 2和Sfrp 5）的缺陷导致小鼠前胃长度减少。在正常的前胃形成过程中，细胞分裂是沿着头尾轴定向的;相反，Sfrps缺陷小鼠的前胃长度减少与肾小管上皮细胞定向细胞分裂的发散有关。因此，定向细胞分裂是前胃形态发生的重要组成部分之一。此外，Sfrps缺陷的小肠上皮不能维持适当的顶基极性。我们还发现，Wnt 5a失活导致的表型类似于Sfrps缺陷在发育中的肠道中诱导的表型，并且Sfrp 1抑制Wnt 5a信号传导。我们建议，Sfrp调控Wnt 5a信号是必需的定向细胞分裂，它调节apicobasal极性在肠道上皮器官伸长。
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.
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