Nephrons are the functional units of the kidney. During kidney development, cells from the cap mesenchyme—a transient kidney-specific progenitor state—undergo a mesenchymal to epithelial transition (MET) and subsequently differentiate into the various epithelial cell types that create the tubular structures of the nephron. Faults in this transition can lead to a pediatric malignancy of the kidney called Wilms’ tumor that mimics normal kidney development. While human kidney development has been characterized at the gene expression level, a comprehensive characterization of alternative splicing is lacking. Therefore, in this study, we performed RNA sequencing on cell populations representing early, intermediate, and late developmental stages of the human fetal kidney, as well as three blastemal-predominant Wilms’ tumor patient-derived xenografts. Using this newly generated RNAseq data, we identified a set of transcripts that are alternatively spliced between the different developmental stages. Moreover, we found that cells from the earliest developmental stage have a mesenchymal splice-isoform profile that is similar to that of blastemal-predominant Wilms’ tumor xenografts. RNA binding motif enrichment analysis suggests that the mRNA binding proteins ESRP1, ESRP2, RBFOX2, and QKI regulate alternative mRNA splicing during human kidney development. These findings illuminate new molecular mechanisms involved in human kidney development and pediatric kidney cancer.
Bibliographical noteFunding Information:
Y.W., I.K., N.B.H., E.B., T.H.B.L., S.O., H.R., Y.Y., and T.K., were supported by the Israel Science Foundation (ICORE no. 1902/12 and Grants no. 1634/13 and 2017/13), the Israel Cancer Association (Grant no. 20150911), the Israel Ministry of Health (Grant no. 3-10146), the EU-FP7 (Marie Curie International Reintegration Grant no. 618592), the Data Science Institute at Bar-Ilan University, and the ICRF (Grant no. 19-101-PG). N.P.S and B.D were supported by the Israel Scientific Foundation (Grant nos. 2071/17 and 910/11). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
© 2022, The Author(s).