Molecular control of smooth muscle cell differentiation in the developing murine ureter

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Structural basis of the contractile activity of the ureter is an outer mesenchymal investment of smooth muscle cells (SMCs) and fibroelastic material. These differentiated cell types arise through a multi-step developmental program from an undifferentiated pool of mesenchymal precursor cells. Although congenital anomalies of the ureteric wall are frequent and may have deleterious consequences for renal function, little is known about the molecular circuits that orchestrate the differentiation of SMCs in the ureteric mesenchyme. In the first funding period we showed by genetic analyses in the mouse, that Hedgehog (HH) signaling is required for proliferation and SMC differentiation of the inner mesenchymal cell layer in the embryonic ureter. These SHH signaling functions are completely mediated by the Forkhead transcription factor FOXF1. FOXF1 activates Bmp4 expression and cooperates with the AKT and SMAD effector pathways of this mesenchymal signal in the further execution of these cellular programs. We identified SRF/GATA6, FGFR2 and PDGFRA as additional factors that positively impact on SMC differentiation whereas retinoic acid signaling was characterized as a pathway that maintains the mesenchymal precursor pool and inhibits SMC differentiation. In the second funding period we want to use a combination of gene targeting studies, pharmacological manipulation of ureter explant cultures, and small and large scale molecular assays to get a deeper understanding about the molecular activation of SMC specific gene expression in the developing ureter. We wish to profile the transcriptional landscape of the developing ureteric mesenchyme, and determine the impact which the SRF/MYOCD transcriptional regulator has on the activation of the SMC specific transcriptome. We wish to further define the molecular function of key signaling pathways in the SMC program. For the SHH-FOXF1-BMP4 module, we want to characterize the molecular regulation of Foxf1 expression, and identify and functionally characterize the direct targets of FOXF1 and SMAD1/5/9-SMAD4 transcriptional activators. We want to determine the molecular consequences of combined RA and BMP4 signaling in maintaining the progenitor state of the ureteric mesenchyme, and investigate the cellular and molecular functions of FGFR2 and PDGFRA signaling in this tissue. Finally, we want to investigate how these signaling pathways are altered in their activity to suppress SMC and favor Lamina propria formation at later stages of ureter development. We expect from these studies new insights in the molecular mechanisms that control SMC differentiation of visceral organs, and into the etiology of congenital obstructive nephropathy.