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

Subject Area Developmental Biology
Term from 2011 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 207786640
 
Final Report Year 2025

Final Report Abstract

Smooth muscle cells (SMCs) are a critical component of the mesenchymal wall of the mammalian ureter, where their contractile activity is responsible for the efficient transport of urine from the renal pelvis to the bladder. SMC fate is universally controlled by the activity of the DNA-binding protein serum response factor (SRF) and its coactivator myocardin (MYOCD). How Myocd expression is transcriptionally activated in the mesenchymal progenitors of the ureteric wall, how and whether SRF and MYOCD influence the expression of (all) SMC structural genes, and how SMC differentiation proceeds in the late fetal and postnatal stages in the ureter is poorly understood. Our previous work showed that during mouse ureter development SHH (and WNT) signals from the epithelial primordium are required for the expression of the transcription factor FOXF1 in the adjacent ureteric mesenchyme. FOXF1, activates and cooperates with BMP4 signaling to induce Myocd expression and SMC differentiation. In contrast, retinoic acid (RA) maintains the progenitor state and inhibits the SMC program. In our project we wanted to further characterize the regulation and function of the SHH- FOXF1-BMP4 module and of RA signaling in Myocd activation in the murine ureter, but also to determine the impact of additional signaling (FGFR2, PDGFRA) and transcription factor activities (GATA2, GATA6, RBPJ, SRF) in this program, in later SMC differentiation and in the divergence of SMCs and lamina propria fibrocytes. Phenotypic analysis of conditionally mutant mice revealed that Gata2, Gata6, the Notch mediator gene Rbpj and Pdgfra are required in the mesenchymal progenitors for the timely expression of Myocd, whereas Fgfr2 acts in the epithelial primordium. GATA2 acts as a feedback inhibitor of RA signaling. GATA6 is a target of BMP4 signaling that cooperates with FOXF1 activity. Pdgfra also inhibits RA signaling whereas FGFR2 enhances Shh expression in the ureteric epithelium. Epithelial FGFR2 signaling is reduced by mesenchymal FGFR2 most likely by limiting FGF ligand availability. Loss of mesenchymal Srf does not affect Myocd expression but abrogates expression of early and late SMC-specific genes. Loss of all of these newly characterized factors results in hydroureter formation at birth. With the exception of the conditional loss of Pdgfra, which leads to distal ureter stenosis, reduced peristalsis due to impaired SMC differentiation is causative. Transcriptional profiling of SMCs in late fetal development has characterized a set of SMC- specific genes that are activated around birth. Expression of these genes is lost in ureters lacking Rbpj in the mesenchyme, suggesting that they depend on (late) Notch signaling. Additional work has shown that the lamina propria arises in late fetal stages and expands during the first postnatal week by matrix deposition and fibrocyte proliferation. SHH and WNT signaling controls the proliferation and differentiation of lamina fibrocytes. It is the absence of BMP4 signaling that accounts for the lineage diversification of LP fibrocytes and SMCs. Taken together, our data provide novel insights into the complex control of Myocd expression and SMC differentiation in the murine ureter. They shed light on hydroureter formation due to functional insufficiency of the mesenchymal wall, and are thus relevant to the etiology of human congenital ureter anomalies.

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