Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90220, Finland.
Biocenter Oulu, Oulu 90220, Finland.
Development. 2022 Nov 1;149(21). doi: 10.1242/dev.201012. Epub 2022 Oct 28.
Kidneys develop via iterative branching of the ureteric epithelial tree and subsequent nephrogenesis at the branch points. Nephrons form in the cap mesenchyme as the metanephric mesenchyme (MM) condenses around the epithelial ureteric buds (UBs). Previous work has demonstrated that FGF8 is important for the survival of nephron progenitor cells (NPCs), and early deletion of Fgf8 leads to the cessation of nephron formation, which results in post-natal lethality. We now reveal a previously unreported function of FGF8. By combining transgenic mouse models, quantitative imaging assays and data-driven computational modelling, we show that FGF8 has a strong chemokinetic effect and that this chemokinetic effect is important for the condensation of NPCs to the UB. The computational model shows that the motility must be lower close to the UB to achieve NPC attachment. We conclude that the FGF8 signalling pathway is crucial for the coordination of NPC condensation at the UB. Chemokinetic effects have also been described for other FGFs and may be generally important for the formation of mesenchymal condensates.
肾脏通过输尿管上皮树的迭代分支以及随后在分支点处的肾发生发育。肾单位在帽状间充质中形成，当中肾间充质（MM）围绕上皮输尿管芽（UB）浓缩时。先前的工作表明，FGF8 对于肾祖细胞（NPC）的存活很重要，并且早期删除 Fgf8 会导致肾单位形成停止，从而导致出生后致死。我们现在揭示了 FGF8 的一个以前未报道的功能。通过结合转基因小鼠模型、定量成像测定和数据驱动的计算建模，我们表明 FGF8 具有很强的趋化运动效应，并且这种趋化运动效应对于 NPC 向 UB 的浓缩很重要。该计算模型表明，为了实现 NPC 附着，靠近 UB 的运动性必须较低。我们得出结论，FGF8 信号通路对于 UB 处 NPC 浓缩的协调至关重要。趋化运动效应也已被描述为其他 FGFs 的作用，并且可能对于间充质浓缩的形成普遍重要。
