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

Ge Gao, Xiaoping Li, Zhixin Jiang, Liliana Osorio, Ying Lam Tang, Xueqing Yu, Guoxiang Jin and Zhongjun Zhou ()
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Ge Gao: Guangdong Academy of Medical Sciences, Southern Medical University
Xiaoping Li: Sun Yat-sen University
Zhixin Jiang: The University of Hong Kong
Liliana Osorio: The University of Hong Kong
Ying Lam Tang: The University of Hong Kong
Xueqing Yu: Guangdong Academy of Medical Sciences, Southern Medical University
Guoxiang Jin: Guangdong Academy of Medical Sciences, Southern Medical University
Zhongjun Zhou: Guangdong Academy of Medical Sciences, Southern Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract 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 α8β1 as a receptor of Ism1 in E11.5 kidney and demonstrate that Ism1 promoted cell-cell adhesion through interacting with Integrin α8β1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-37992-x

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