Institute of Biomedicine/Medical Biochemistry and Developmental Biology, Biomedicum Helsinki, PO Box 63, FI-00014 University of Helsinki, Finland.
Differentiation. 2011 Feb;81(2):81-91. doi: 10.1016/j.diff.2010.10.001. Epub 2010 Oct 30.
Semaphorins, originally identified as axon guidance molecules, have also been implicated in angiogenesis, function of the immune system and cancerous growth. Here we show that deletion of Plexin B2 (Plxnb2), a semaphorin receptor that is expressed both in the pretubular aggregates and the ureteric epithelium in the developing kidney, results in renal hypoplasia and occasional double ureters. The rate of cell proliferation in the ureteric epithelium and consequently the number of ureteric tips are reduced in the kidneys lacking Plexin B2 (Plxnb2-/-). Semaphorin 4C, a ligand for Plexin B2, stimulates branching of the ureteric epithelium in wild type and Plxnb2+/- kidney explants, but not in Plxnb2-/- explants. As shown by co-immunoprecipitation Plexin B2 interacts with the Ret receptor tyrosine kinase, the receptor of Glial-cell-line-derived neurotrophic factor (Gdnf), in embryonic kidneys. Isolated Plxnb2-/- ureteric buds fail to respond to Gdnf by branching, but this response is rescued by Fibroblast growth factor 7 and Follistatin as well as by the metanephric mesenchyme. The differentiation of the nephrogenic mesenchyme, its morphology and the rate of apoptosis in the Plxnb2-/- kidneys are normal. Plexin B2 is co-expressed with Plexin B1 (Plxnb1) in the kidney. The double homozygous Plxnb1-Plxnb2-deficient mice show high embryonic lethality prior to onset of nephrogenesis. The only double homozygous embryo surviving to E12 showed hypoplastic kidneys with ureteric branches and differentiating mesenchyme. Taken together, our results show that Sema4C-Plexin B2 signalling regulates ureteric branching, possibly through modulation of Gdnf signalling by interaction with Ret, and suggest non-redundant roles for Plexin B1 and Plexin B2 in kidney development.
神经信号素最初被鉴定为轴突导向分子，也参与了血管生成、免疫系统功能和癌症生长。在这里，我们表明，在发育中的肾脏中，表达于肾小管丛和输尿管上皮的神经信号素受体 Plexin B2（Plxnb2）缺失会导致肾脏发育不良和偶尔出现双输尿管。缺乏 Plexin B2（Plxnb2-/-）的肾脏中，输尿管上皮的细胞增殖速度降低，因此输尿管尖端的数量减少。神经信号素 4C 是 Plexin B2 的配体，它可以刺激野生型和 Plxnb2+/-肾脏外植体的输尿管上皮分支，但不能刺激 Plxnb2-/-外植体的分支。免疫共沉淀表明，在胚胎肾脏中，Plexin B2 与 Ret 受体酪氨酸激酶相互作用，Ret 是神经胶质细胞源性神经营养因子（Gdnf）的受体。分离的 Plxnb2-/-输尿管芽不能通过分支对 Gdnf 做出反应，但这种反应可以通过成纤维细胞生长因子 7 和卵泡抑素以及中肾间充质来挽救。Plxnb2-/-肾脏的肾发生间充质分化、形态和细胞凋亡率正常。Plexin B2 与 Plexin B1（Plxnb1）在肾脏中共同表达。Plexin B1 和 Plexin B2 双重纯合缺陷小鼠在肾发生前发生高胚胎致死性。唯一存活到 E12 的双重纯合胚胎显示出具有输尿管分支和分化间充质的发育不良的肾脏。总之，我们的结果表明，Sema4C-Plexin B2 信号调节输尿管分支，可能通过与 Ret 的相互作用调节 Gdnf 信号，并且表明 Plexin B1 和 Plexin B2 在肾脏发育中具有非冗余作用。
