2. Academic Validation
  3. Isthmin-1 (Ism1) modulates renal branching morphogenesis and mesenchyme condensation during early kidney development

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

  • Nat Commun. 2023 Apr 25;14(1):2378. doi: 10.1038/s41467-023-37992-x.
Ge Gao # 1 2,  Xiaoping Li # 3,  Zhixin Jiang 2,  Liliana Osorio 2,  Ying Lam Tang 2,  Xueqing Yu 1,  Guoxiang Jin 1,  Zhongjun Zhou 4 5 6
Affiliations

Affiliations

  • 1 Guangdong Cardiovascular Institute, Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China.
  • 2 School of Biomedical Sciences, LKS Faculty of medicine, The University of Hong Kong, Hong Kong, China.
  • 3 Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital, Organ Transplantation Institute, Sun Yat-sen University, Guangzhou, 510630, Guangdong, China.
  • 4 Guangdong Cardiovascular Institute, Medical Research Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, 510080, China. [email protected].
  • 5 School of Biomedical Sciences, LKS Faculty of medicine, The University of Hong Kong, Hong Kong, China. [email protected].
  • 6 Reproductive Medical Center, The University of Hong Kong - Shenzhen Hospital, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 37185772 DOI: 10.1038/s41467-023-37992-x
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.

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