Institute of Molecular Biology, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Institute of Clinical Biochemistry, Medizinische Hochschule Hannover, 30625 Hannover, Germany.
Development. 2022 Sep 1;149(17). doi: 10.1242/dev.200767. Epub 2022 Sep 12.
The coordinated development of the mesenchymal and epithelial progenitors of the murine ureter depends on a complex interplay of diverse signaling activities. We have recently shown that epithelial FGFR2 signaling regulates stratification and differentiation of the epithelial compartment by enhancing epithelial Shh expression, and mesenchymal SHH and BMP4 activity. Here, we show that FGFR1 and FGFR2 expression in the mesenchymal primordium impinges on the SHH/BMP4 signaling axis to regulate mesenchymal patterning and differentiation. Mouse embryos with conditional loss of Fgfr1 and Fgfr2 in the ureteric mesenchyme exhibited reduced mesenchymal proliferation and prematurely activated lamina propria formation at the expense of the smooth muscle cell program. They also manifested hydroureter at birth. Molecular profiling detected increased SHH, WNT and retinoic acid signaling, whereas BMP4 signaling in the mesenchyme was reduced. Pharmacological activation of SHH signaling in combination with inhibition of BMP4 signaling recapitulated the cellular changes in explant cultures of wild-type ureters. Additional experiments suggest that mesenchymal FGFR1 and FGFR2 act as a sink for FGF ligands to dampen activation of Shh and BMP receptor gene expression by epithelial FGFR2 signaling.
小鼠输尿管的中胚层和上皮祖细胞的协调发育依赖于多种信号活动的复杂相互作用。我们最近表明，上皮 FGFR2 信号通过增强上皮 Shh 表达以及中胚层 SHH 和 BMP4 活性来调节上皮细胞的分层和分化。在这里，我们表明中胚层原始细胞中 FGFR1 和 FGFR2 的表达会影响 SHH/BMP4 信号轴，从而调节中胚层的模式形成和分化。在输尿管中胚层条件性缺失 Fgfr1 和 Fgfr2 的小鼠胚胎表现出减少的中胚层增殖，并过早地激活固有层形成，而平滑肌细胞程序受损。它们在出生时也表现出尿积水。分子谱分析检测到 SHH、WNT 和视黄酸信号增加，而中胚层的 BMP4 信号减少。SHH 信号的药理学激活与 BMP4 信号的抑制相结合，在野生型输尿管的外植体培养中再现了细胞变化。其他实验表明，中胚层 FGFR1 和 FGFR2 充当 FGF 配体的汇，以抑制上皮 FGFR2 信号对 Shh 和 BMP 受体基因表达的激活。
