TY - BOOK

T1 - Molecular control of murine ureter development

T2 - The function of FGF and BMP4 signaling

AU - Deuper, Lena

N1 - Doctoral thesis

PY - 2023

Y1 - 2023

N2 - The ureters are muscular tubes that propel the urine from the renal pelvis to the bladder by uni-directional peristaltic contractions. To fulfill this function the ureters are compartmentalized into an outer mesenchymal wall with layers of fibrocytes in the inner lamina propria (LP) and the outer tunica adventitia (TA) unsheathing smooth muscle cells (SMC), and an inner highly spe-cialized epithelium: the urothelium. The urothelium features a three-layered organization of su-perficial (S), intermediate (I) and basal (B) cells. The ureteric mesenchyme (UM) as well as the ureteric epithelium (UE) arise from pools of homogeneous, uncommitted precursor cells. Pat-terning, proliferation and differentiation of these progenitors rely on a very complex interplay of various signaling pathways. SHH and WNT signals from the UE and BMP4 from the UM pro-mote epithelial and mesenchymal proliferation and differentiation. In contrast, retinoic acid (RA) within the UM and the UE inhibits differentiation and promotes precursor proliferation in both compartments. How these signals cooperate with each other and possibly additional as yet unknown signals and how they impinge on various transcription factor (TF) genes to control the development of three different cell types from homogeneous precursor cell populations in two different tissue compartments is poorly understood. Aim of this thesis was to address the func-tion of FGF and BMP4 signaling in this context. Expression of Fgfr1 and Fgfr2 was found in the undifferentiated UE as well as in the surround-ing UM. Targeted inactivation of Fgfr2 in the UE resulted in loss of I and B cells, delayed onset of SMC differentiation and in an inability to form the LP. Fgfr2 was found to increase SHH and BMP4 signaling to allow differentiation of epithelial cells and to precisely activate SMC differen-tiation. FGFRs in the mesenchyme act as a molecular sink to fine tune this signaling axis. Tar-geted ablation of Fgfr1 and Fgfr2 delayed the onset of SMC differentiation and led to premature development of the LP. Pharmacological rescue and gain of function experiments showed that increased SHH and BMP4 signaling promote I and B cell as well as SMC differentiation, while increased SHH but decreased BMP4 signaling promotes LP development. BMP4 signaling was previously described to act on the development of the UE and the UM but the transcriptional targets remained widely unexplored. Genetic and pharmacological inactiva-tion of BMP4 signaling identified TF genes differentially controlling the development of the UM and UE. Molecular inspection unraveled that some of these TF genes were regulated as a con-sequence of increased RA signaling in Bmp4 mutant ureters. This thesis identified FGF signaling as a crucial regulator of signaling networks controlling tem-poral and spatial differentiation of the murine ureter and increased our knowledge of the molec-ular function of BMP4 signaling in the context of ureter development

AB - The ureters are muscular tubes that propel the urine from the renal pelvis to the bladder by uni-directional peristaltic contractions. To fulfill this function the ureters are compartmentalized into an outer mesenchymal wall with layers of fibrocytes in the inner lamina propria (LP) and the outer tunica adventitia (TA) unsheathing smooth muscle cells (SMC), and an inner highly spe-cialized epithelium: the urothelium. The urothelium features a three-layered organization of su-perficial (S), intermediate (I) and basal (B) cells. The ureteric mesenchyme (UM) as well as the ureteric epithelium (UE) arise from pools of homogeneous, uncommitted precursor cells. Pat-terning, proliferation and differentiation of these progenitors rely on a very complex interplay of various signaling pathways. SHH and WNT signals from the UE and BMP4 from the UM pro-mote epithelial and mesenchymal proliferation and differentiation. In contrast, retinoic acid (RA) within the UM and the UE inhibits differentiation and promotes precursor proliferation in both compartments. How these signals cooperate with each other and possibly additional as yet unknown signals and how they impinge on various transcription factor (TF) genes to control the development of three different cell types from homogeneous precursor cell populations in two different tissue compartments is poorly understood. Aim of this thesis was to address the func-tion of FGF and BMP4 signaling in this context. Expression of Fgfr1 and Fgfr2 was found in the undifferentiated UE as well as in the surround-ing UM. Targeted inactivation of Fgfr2 in the UE resulted in loss of I and B cells, delayed onset of SMC differentiation and in an inability to form the LP. Fgfr2 was found to increase SHH and BMP4 signaling to allow differentiation of epithelial cells and to precisely activate SMC differen-tiation. FGFRs in the mesenchyme act as a molecular sink to fine tune this signaling axis. Tar-geted ablation of Fgfr1 and Fgfr2 delayed the onset of SMC differentiation and led to premature development of the LP. Pharmacological rescue and gain of function experiments showed that increased SHH and BMP4 signaling promote I and B cell as well as SMC differentiation, while increased SHH but decreased BMP4 signaling promotes LP development. BMP4 signaling was previously described to act on the development of the UE and the UM but the transcriptional targets remained widely unexplored. Genetic and pharmacological inactiva-tion of BMP4 signaling identified TF genes differentially controlling the development of the UM and UE. Molecular inspection unraveled that some of these TF genes were regulated as a con-sequence of increased RA signaling in Bmp4 mutant ureters. This thesis identified FGF signaling as a crucial regulator of signaling networks controlling tem-poral and spatial differentiation of the murine ureter and increased our knowledge of the molec-ular function of BMP4 signaling in the context of ureter development

U2 - 10.15488/13536

DO - 10.15488/13536

M3 - Doctoral thesis

CY - Hannover

ER -