Isthmin-1 (Ism1) modulates renal branching morphogenesis and mesenchyme condensation during early kidney development

作者：Gao, Ge; Li, Xiaoping; Jiang, Zhixin; Osorio, Liliana; Tang, Ying Lam; Yu, Xueqing; Jin, Guoxiang; Zhou, Zhongjun^*

来源：Nature Communications, 2023, 14(1): 2378.

DOI：10.1038/s41467-023-37992-x

• IN-SITU HYBRIDIZATION
• EXTRACELLULAR-MATRIX
• PROTEIN NEPHRONECTIN
• MICE
• BETA-1-INTEGRIN
• IDENTIFICATION
• TYPE-1
• ALPHA
• GENE
• MAINTENANCE

Loss of Ism1 in mice results in kidney agenesis and dysplasia that are common human diseases. Here they show that Ism1 is expressed in metanephric mesenchyme and acts as a ligand of Integrin alpha 8 beta 1 to regulate mesenchyme condensation during early renal branching morphogenesis. @@@ The outgrowth of epithelial bud followed by reiterated bifurcations during renal development is driven by the ligand-receptor interactions between the epithelium and the surrounding mesenchyme. Here, by exploring ligand-receptor interactions in E10.5 and E11.5 kidneys by single cell RNA-seq, we find that Isthmin1 (Ism1), a secreted protein, resembles Gdnf expression and modulates kidney branching morphogenesis. Mice deficient for Ism1 exhibit defective ureteric bud bifurcation and impaired metanephric mesenchyme condensation in E11.5 embryos, attributable to the compromised Gdnf/Ret signaling, ultimately leading to renal agenesis and hypoplasia/dysplasia. By HRP-induced proximity labelling, we further identify integrin alpha 8 beta 1 as a receptor of Ism1 in E11.5 kidney and demonstrate that Ism1 promoted cell-cell adhesion through interacting with Integrin alpha 8 beta 1, the receptor whose activation is responsible for Gdnf expression and mesenchyme condensation. Taken together, our work reveals Ism1 as a critical regulator of cell-cell interaction that modulates Gdnf/Ret signaling during early kidney development.

• 单位
  广东省心血管病研究所; 南方医科大学; 广东省人民医院; 中山大学