Transcription Factors YAP/TAZ and SRF Cooperate To Specify Renal Myofibroblasts in the Developing Mouse Kidney. Issue 9 (September 2022)

• Record Type: Journal Article
• Authors: Drake, Keri A.; Chaney, Christopher; Patel, Mohita; Das, Amrita; Bittencourt, Julia; Cohn, Martin; Carroll, Thomas J.
• Is Part Of: Journal of the American Society of Nephrology. Volume 33:Issue 9(2022)
• Page Start: 1694
• Page End: 1707
• Publication Date: 2022-09
• Subjects: Hippo/Warts -- pericyte -- fibroblast heterogeneity -- stromal microenvironment -- kidney development -- myofibroblasts
• DOI: 10.1681/ASN.2021121559
• Languages: English
• ISSNs: 1046-6673

Abstract

Significance Statement: Embryonic renal interstitial cells give rise to multiple cell types in the adult, including fibroblasts, myofibroblasts, mural cells, and smooth muscle. How the different cell types arise from a multipotent progenitor is unknown. In this study, the authors identified a subpopulation of stromal cells in mouse embryonic kidneys with enriched activity in the transcriptional regulators YAP and TAZ, and show that YAP/TAZ and the transcriptional regulator SRF have independent and codependent roles in the specification of unique subsets of interstitial cells. These findings offer insights into the role of the interstitium in kidney development and may inform efforts aimed at regenerating renal tissue and may aid efforts to understand the drivers of kidney fibrosis. Visual Abstract: Abstract : Background: The embryonic renal stroma consists of multiple molecularly distinct cell subpopulations, the functional significance of which is largely unknown. Previous work has demonstrated that the transcription factors YAP and TAZ play roles in the development and morphogenesis of the nephrons, collecting ducts, and nephron progenitor cells. Methods: In embryonic mouse kidneys, we identified a subpopulation of stromal cells with enriched activity in YAP and TAZ. To evaluate the function of these cell types, we genetically ablated both Yap and Taz from the stromal progenitor population and examined how gene activity and development of YAP/TAZ mutant kidneys are affected over a developmental time course. Results: We found that YAP and TAZ are active in a subset of renal interstitium and that stromal-specific coablation of YAP/TAZ disrupts cortical fibroblast, pericyte, and myofibroblast development, with secondary effects on peritubular capillary differentiation. We also demonstrated that the transcription factor SRF cooperates with YAP/TAZ to drive expression of at least a subset of renal myofibroblast target genes and to specify myofibroblasts but not cortical fibroblasts or pericytes. Conclusions: These findings reveal a critical role for YAP/TAZ in specific embryonic stromal cells and suggest that interaction with cofactors, such as SRF, influence the expression of cell type–specific target genes, thus driving stromal heterogeneity. Further, this work reveals functional roles for renal stroma heterogeneity in creating unique microenvironments that influence the differentiation and maintenance of the renal parenchyma.