Lin Y, Zhang S, Rehn M, Itäranta P, Tuukkanen J, Heljäsvaara R, Peltoketo H, Pihlajaniemi T, Vainio S
Biocenter Oulu and Department of Biochemistry, University of Oulu, Linnanmaa, FIN-90570 Oulu, Finland.
Development. 2001 May;128(9):1573-85. doi: 10.1242/dev.128.9.1573.
Epithelial-mesenchymal tissue interactions regulate the formation of signaling centers that play a role in the coordination of organogenesis, but it is not clear how their activity leads to differences in organogenesis. We report that type XVIII collagen, which contains both a frizzled and an endostatin domain, is expressed throughout the respective epithelial bud at the initiation of lung and kidney organogenesis. It becomes localized to the epithelial tips in the lung during the early stages of epithelial branching, while its expression in the kidney is confined to the epithelial stalk region and is lost from the nearly formed ureter tips, thus displaying the reverse pattern to that in the lung. In recombinants, between ureter bud and lung mesenchyme, type XVIII collagen expression pattern in the ureter bud shifts from the kidney to the lung type, accompanied by a shift in sonic hedgehog expression in the epithelium. The lung mesenchyme is also sufficient to induce ectopic lung surfactant protein C expression in the ureter bud. Moreover, the shift in type XVIII collagen expression is associated with changes in ureter development, thus resembling aspects of early lung type epigenesis in the recombinants. Respecification of collagen is necessary for the repatterning process, as type XVIII collagen antibody blocking had no effect on ureter development in the intact kidney, whereas it reduced the number of epithelial tips in the lung and completely blocked ureter development with lung mesenchyme. Type XVIII collagen antibody blocking also led to a notable reduction in the expression of Wnt2, which is expressed in the lung mesenchyme but not in that of the kidney, suggesting a regulatory interaction between this collagen and Wnt2. Respecification also occurred in a chimeric organ containing the ureter bud and both kidney and lung mesenchymes, indicating that the epithelial tips can integrate the morphogenetic signals independently. A glial cell line-derived neurotrophic factor signal induces loss of type XVIII collagen from the ureter tips and renders the ureter bud competent for repatterning by lung mesenchyme-derived signals. Our data suggest that differential organ morphogenesis is regulated by an intra-organ patterning process that involves coordination between inductive signals and matrix molecules, such as type XVIII collagen.
上皮-间充质组织相互作用调节信号中心的形成，这些信号中心在器官发生的协调中发挥作用，但尚不清楚它们的活性如何导致器官发生的差异。我们报告称，含有卷曲蛋白和内皮抑素结构域的 XVIII 型胶原蛋白在肺和肾器官发生起始时在各自的上皮芽中均有表达。在肺上皮分支的早期阶段，它定位于肺上皮尖端，而其在肾中的表达局限于上皮茎区域，并在即将形成的输尿管尖端消失，从而呈现出与肺中相反的模式。在输尿管芽与肺间充质的重组体中，输尿管芽中 XVIII 型胶原蛋白的表达模式从肾型转变为肺型，同时上皮中 Sonic hedgehog 的表达也发生了转变。肺间充质也足以诱导输尿管芽中异位的肺表面活性物质蛋白 C 的表达。此外，XVIII 型胶原蛋白表达的转变与输尿管发育的变化相关，因此类似于重组体中早期肺型表观遗传的某些方面。胶原蛋白的重新指定对于重新模式化过程是必要的，因为 XVIII 型胶原蛋白抗体阻断对完整肾脏中的输尿管发育没有影响，而它减少了肺中的上皮尖端数量，并完全阻断了与肺间充质一起时的输尿管发育。XVIII 型胶原蛋白抗体阻断还导致 Wnt2 的表达显著降低，Wnt2 在肺间充质中表达但不在肾间充质中表达，这表明这种胶原蛋白与 Wnt2 之间存在调节相互作用。重新指定也发生在包含输尿管芽以及肾和肺间充质的嵌合器官中，表明上皮尖端可以独立整合形态发生信号。一种胶质细胞系源性神经营养因子信号诱导输尿管尖端丢失 XVIII 型胶原蛋白，并使输尿管芽能够被肺间充质衍生的信号重新模式化。我们的数据表明，不同器官的形态发生受器官内模式化过程的调节，该过程涉及诱导信号与基质分子（如 XVIII 型胶原蛋白）之间的协调。
