Cadherin adhesion complexes direct cell aggregation in the epithelial transition of Wnt-induced nephron progenitor cells.

IF 3.7 2区生物学 Q1 DEVELOPMENTAL BIOLOGY Development Pub Date : 2024-09-15 Epub Date: 2024-09-30 DOI:10.1242/dev.202303

Balint Der, Helena Bugacov, Bohdana-Myroslava Briantseva, Andrew P McMahon

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Abstract

In the developing mammalian kidney, nephron formation is initiated by a subset of nephron progenitor cells (NPCs). Wnt input activates a β-catenin (Ctnnb1)-driven, transcriptional nephrogenic program and the mesenchymal to epithelial transition (MET) of NPCs. Using an in vitro mouse NPC culture model, we observed that activation of the Wnt pathway results in the aggregation of induced NPCs, which is an initiating step in the MET program. Genetic removal showed aggregation was dependent on β-catenin. Modulating extracellular Ca2+ levels showed cell-cell contacts were Ca2+ dependent, suggesting a role for cadherin (Cdh)-directed cell adhesion. Molecular analysis identified Cdh2, Cdh4 and Cdh11 in NPCs, and the β-catenin directed upregulation of Cdh3 and Cdh4 accompanying the MET of induced NPCs. Mutational analysis of β-catenin supported a role for a Lef/Tcf-β-catenin-mediated transcriptional response in the cell aggregation process. Genetic removal of all four cadherins, and independent removal of α-catenin or of β-catenin-α-catenin interactions, abolished aggregation, but not the inductive response to Wnt pathway activation. These findings, and data in an accompanying article highlight the role of β-catenin in linking transcriptional programs to the morphogenesis of NPCs in mammalian nephrogenesis.

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在 Wnt 诱导的肾祖细胞上皮转化过程中，粘附素粘附复合物引导细胞聚集。

在发育中的哺乳动物肾脏中，肾小球的形成是由肾小球祖细胞（NPC）的一个亚群启动的。Wnt输入激活了β-catenin（Ctnnb1）驱动的转录肾原性程序和NPC的间充质向上皮转化（MET）。通过体外小鼠鼻咽癌培养模型，我们观察到 Wnt 通路的激活会导致诱导的鼻咽癌聚集，这是 MET 程序的启动步骤。基因清除显示聚集依赖于β-catenin。调节细胞外Ca2+水平显示细胞-细胞接触依赖于Ca2+，这表明由粘附素（Cdh）引导的细胞粘附发挥作用。分子分析确定了鼻咽癌细胞中的 Cdh2、Cdh4 和 Cdh11，β-catenin 引导的 Cdh3 和 Cdh4 上调伴随着诱导鼻咽癌细胞的 MET。β-catenin的突变分析支持Lef/Tcf-β-catenin介导的转录反应在细胞聚集过程中的作用。通过基因移除所有四种粘附蛋白，以及独立移除α-catenin或β-catenin-α-catenin相互作用，可消除聚集，但不能消除对Wnt通路激活的诱导反应。这些发现以及随附文章中的数据强调了β-catenin在哺乳动物肾形成过程中将转录程序与NPC的形态发生联系起来的作用。

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来源期刊

Development 生物-发育生物学

CiteScore

6.70

自引率

4.30%

发文量

433

审稿时长

3 months

期刊介绍： Development’s scope covers all aspects of plant and animal development, including stem cell biology and regeneration. The single most important criterion for acceptance in Development is scientific excellence. Research papers (articles and reports) should therefore pose and test a significant hypothesis or address a significant question, and should provide novel perspectives that advance our understanding of development. We also encourage submission of papers that use computational methods or mathematical models to obtain significant new insights into developmental biology topics. Manuscripts that are descriptive in nature will be considered only when they lay important groundwork for a field and/or provide novel resources for understanding developmental processes of broad interest to the community. Development includes a Techniques and Resources section for the publication of new methods, datasets, and other types of resources. Papers describing new techniques should include a proof-of-principle demonstration that the technique is valuable to the developmental biology community; they need not include in-depth follow-up analysis. The technique must be described in sufficient detail to be easily replicated by other investigators. Development will also consider protocol-type papers of exceptional interest to the community. We welcome submission of Resource papers, for example those reporting new databases, systems-level datasets, or genetic resources of major value to the developmental biology community. For all papers, the data or resource described must be made available to the community with minimal restrictions upon publication. To aid navigability, Development has dedicated sections of the journal to stem cells & regeneration and to human development. The criteria for acceptance into these sections is identical to those outlined above. Authors and editors are encouraged to nominate appropriate manuscripts for inclusion in one of these sections.