Deciphering the Cellular and Molecular Landscapes of Wnt/β-catenin Signaling in Mouse Embryonic Kidney Development

Overview

Journal Comput Struct Biotechnol J

Specialty Biotechnology

Date 2024 Sep 23

PMID 39310276

Authors

Hui Zhao

Hui Gong

Peide Zhu

Chang Sun

Wuping Sun

Yujin Zhou

Xiaoxiao Wu

Ailin Qiu

Xiaosha Wen

Jinde Zhang

Dixian Luo

Quan Liu

Yifan Li

Affiliations

Soon will be listed here.

Abstract

Background: The Wnt/β-catenin signaling pathway is critical in kidney development, yet its specific effects on gene expression in different embryonic kidney cell types are not fully understood.

Methods: Wnt/β-catenin signaling was activated in mouse E12.5 kidneys using CHIR99021, with RNA sequencing performed afterward, and the results were compared to DMSO controls (dataset GSE131240). Differential gene expression in ureteric buds and cap mesenchyme following pathway activation (datasets GSE20325 and GSE39583) was analyzed. Single-cell RNA-seq data from the Mouse Cell Atlas was used to link differentially expressed genes (DEGs) with kidney cell types. β-catenin ChIP-seq data (GSE39837) identified direct transcriptional targets.

Results: Activation of Wnt/β-catenin signaling led to 917 significant DEGs, including the upregulation of and and the downregulation of and . These DEGs were involved in kidney development and immune response. Single-cell analysis identified 787 DEGs across nineteen cell subtypes, with Macrophage_Apoe high cells showing the most pronounced enrichment of Wnt/β-catenin-activated genes. Gene expression profiles in ureteric buds and cap mesenchyme differed significantly upon β-catenin manipulation, with cap mesenchyme showing a unique set of DEGs. Analysis of β-catenin ChIP-seq data revealed 221 potential direct targets, including and .

Conclusion: This study maps the complex gene expression driven by Wnt/β-catenin signaling in embryonic kidney cell types. The identified DEGs and β-catenin targets elucidate the molecular details of kidney development and the pathway's role in immune processes, providing a foundation for further research into Wnt/β-catenin signaling in kidney development and disease.

References

Hu M, Piscione T, Rosenblum N . Elevated SMAD1/beta-catenin molecular complexes and renal medullary cystic dysplasia in ALK3 transgenic mice. Development. 2003; 130(12):2753-66. DOI: 10.1242/dev.00478. View

Carroll T, Park J, Hayashi S, Majumdar A, McMahon A . Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell. 2005; 9(2):283-92. DOI: 10.1016/j.devcel.2005.05.016. View

Abnave P, Ghigo E . Role of the immune system in regeneration and its dynamic interplay with adult stem cells. Semin Cell Dev Biol. 2018; 87:160-168. DOI: 10.1016/j.semcdb.2018.04.002. View

Schon S, Flierman I, Ofner A, Stahringer A, Holdt L, Kolligs F . β-catenin regulates NF-κB activity via TNFRSF19 in colorectal cancer cells. Int J Cancer. 2014; 135(8):1800-11. DOI: 10.1002/ijc.28839. View

Mohri Y, Oyama K, Akamatsu A, Kato S, Nishimori K . Lgr4-deficient mice showed premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3. Dev Dyn. 2011; 240(6):1626-34. DOI: 10.1002/dvdy.22651. View

Yu L, Xie M, Zhang F, Wan C, Yao X . TM9SF4 is a novel regulator in lineage commitment of bone marrow mesenchymal stem cells to either osteoblasts or adipocytes. Stem Cell Res Ther. 2021; 12(1):573. PMC: 8590266. DOI: 10.1186/s13287-021-02636-8. View

Billfeldt N, Banyai D, Kovacs G . Absence of Canonical WNT Signaling in Adult Renal Cell Tumors of Embryonal Origin. Anticancer Res. 2016; 36(5):2169-73. View

Munro D, Hughes J . The Origins and Functions of Tissue-Resident Macrophages in Kidney Development. Front Physiol. 2017; 8:837. PMC: 5660965. DOI: 10.3389/fphys.2017.00837. View

Fei L, Chen H, Ma L, E W, Wang R, Fang X . Systematic identification of cell-fate regulatory programs using a single-cell atlas of mouse development. Nat Genet. 2022; 54(7):1051-1061. DOI: 10.1038/s41588-022-01118-8. View

10.

Wang Z, Wu Z, Wang H, Feng R, Wang G, Li M . An immune cell atlas reveals the dynamics of human macrophage specification during prenatal development. Cell. 2023; 186(20):4454-4471.e19. DOI: 10.1016/j.cell.2023.08.019. View

11.

Stark K, Vainio S, Vassileva G, McMahon A . Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 1994; 372(6507):679-83. DOI: 10.1038/372679a0. View

12.

Taguchi A, Nishinakamura R . Higher-Order Kidney Organogenesis from Pluripotent Stem Cells. Cell Stem Cell. 2017; 21(6):730-746.e6. DOI: 10.1016/j.stem.2017.10.011. View

13.

Xiao L, Zhou D, Tan R, Fu H, Zhou L, Hou F . Sustained Activation of Wnt/β-Catenin Signaling Drives AKI to CKD Progression. J Am Soc Nephrol. 2015; 27(6):1727-40. PMC: 4884114. DOI: 10.1681/ASN.2015040449. View

14.

Andl T, Zhang Y . Reaping Wnt after calming Hippo: Wnt and Hippo signaling cross paths in lung cancer. J Thorac Dis. 2017; 9(11):4174-4179. PMC: 5720977. DOI: 10.21037/jtd.2017.10.29. View

15.

Kispert A, Vainio S, McMahon A . Wnt-4 is a mesenchymal signal for epithelial transformation of metanephric mesenchyme in the developing kidney. Development. 1998; 125(21):4225-34. DOI: 10.1242/dev.125.21.4225. View

16.

Yu J, Carroll T, Rajagopal J, Kobayashi A, Ren Q, McMahon A . A Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney. Development. 2008; 136(1):161-71. PMC: 2685965. DOI: 10.1242/dev.022087. View

17.

Boivin F, Sarin S, Lim J, Javidan A, Svajger B, Khalili H . Stromally expressed β-catenin modulates Wnt9b signaling in the ureteric epithelium. PLoS One. 2015; 10(3):e0120347. PMC: 4372213. DOI: 10.1371/journal.pone.0120347. View

18.

Schumacher A, Rookmaaker M, Joles J, Kramann R, Nguyen T, van Griensven M . Defining the variety of cell types in developing and adult human kidneys by single-cell RNA sequencing. NPJ Regen Med. 2021; 6(1):45. PMC: 8357940. DOI: 10.1038/s41536-021-00156-w. View

19.

Martin-Carro B, Martin-Virgala J, Fernandez-Villabrille S, Fernandez-Fernandez A, Perez-Basterrechea M, Navarro-Gonzalez J . Role of Klotho and AGE/RAGE-Wnt/β-Catenin Signalling Pathway on the Development of Cardiac and Renal Fibrosis in Diabetes. Int J Mol Sci. 2023; 24(6). PMC: 10049403. DOI: 10.3390/ijms24065241. View

20.

Bridgewater D, Di Giovanni V, Cain J, Cox B, Jakobson M, Sainio K . β-catenin causes renal dysplasia via upregulation of Tgfβ2 and Dkk1. J Am Soc Nephrol. 2011; 22(4):718-31. PMC: 3065227. DOI: 10.1681/ASN.2010050562. View