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Expression of Wnt signaling proteins in rare congenital bladder disorders
Boyu Xie1, Michael Millar2, Callum Arthurs1
1Centre for Gene Therapy and Regenerative Medicine, Guy's Hospital, Great Maze Pond, King's College London, London SE1 9RT, UK.
Introduction And Aims:
Congenital bladder anomalies are rare and are a leading cause of end stage renal failure in children. The Wnt signaling pathway, important during embryonic development, has been implicated in the pathogenesis of these conditions through regulation of gene expression, including essential transcription factors. We investigated the expression of four Wnt transcriptional targets, namely, Pygopus 1 (Pygo1), Connexin 43 (Cx43), FRA1 and TCF7L1 in three rare congenital bladder disorders: bladder exstrophy (BE), neurogenic bladder (NGB) and posterior urethral valves (PUV).
Methods:
Bladder tissue samples were collected from patients at the Great Ormond Street Hospital for Sick Children, London, UK, with control (normally-functioning bladder, N = 9), BE (N = 15), NGB (N = 6) and PUV (N = 5). Histological analysis was performed using the van Gieson stain to differentiate smooth muscle (SM) and connective tissue (CT) compartments. An unbiased, automated, semi-quantitative immunofluorescence analysis was performed to measure the labelling intensity of four Wnt-related proteins in tissue from these four groups.
Results And Discussion:
There was a significant (p < 0.05) increase in the expression of Pygo1 in the smooth muscle of all anomalies examined and also in the connective tissue in PUV compared to control. Cx43 also showed overexpression in the smooth muscle across all conditions; however, there was a reduced expression in NGB and an increase in PUV in connective tissue. TCF7L1 showed a significant decrease in both tissue compartments for NGB, whereas FRA1 expression remained unchanged across all anomalies. We also measured colocalization of Wnt-related proteins. TCF7L1 exhibited increased colocalization with Pygo1 and FRA1 in exstrophy compared to control. These results suggest a complex dysregulation of the Wnt pathway in congenital bladder disorders.
Conclusion:
Wnt signaling-related proteins show dysregulation in congenital bladder disorders compared to control tissue. Understanding these mechanisms should help towards non-invasive early diagnosis, drug target discovery and development of treatment strategies for these conditions.
Insights
Congenital bladder disorders show altered Wnt signaling pathway proteins, including Pygopus 1 (Pygo1) and Connexin 43 (Cx43), compared to healthy bladders. These findings suggest complex pathway dysregulation in conditions like bladder exstrophy (BE), neurogenic bladder (NGB), and posterior urethral valves (PUV).
Area of Science:
- Developmental Biology
- Molecular Biology
- Urology
Background:
- Congenital bladder anomalies are rare but a major cause of pediatric end-stage renal failure.
- The Wnt signaling pathway is crucial for embryonic development and implicated in these disorders.
- Key Wnt transcriptional targets are investigated in bladder exstrophy (BE), neurogenic bladder (NGB), and posterior urethral valves (PUV).
Purpose of the Study:
- To investigate the expression of Wnt signaling pathway targets Pygopus 1 (Pygo1), Connexin 43 (Cx43), FRA1, and TCF7L1.
- To compare protein expression in congenital bladder anomalies versus control bladder tissue.
- To understand the role of Wnt pathway dysregulation in the pathogenesis of congenital bladder disorders.
Main Methods:
- Bladder tissue samples were collected from patients with BE, NGB, PUV, and controls.
- Histological analysis using van Gieson stain differentiated smooth muscle and connective tissue.
- Automated immunofluorescence quantified Wnt-related protein labeling intensity.
Main Results:
- Pygo1 and Cx43 showed increased expression in smooth muscle across all anomalies.
- TCF7L1 expression decreased significantly in NGB, while FRA1 remained unchanged.
- Increased colocalization of TCF7L1 with Pygo1 and FRA1 was observed in bladder exstrophy.
Conclusions:
- Wnt signaling pathway proteins are dysregulated in congenital bladder disorders.
- These findings suggest complex molecular mechanisms underlying these conditions.
- Understanding Wnt pathway dysregulation may aid in early diagnosis and treatment development.
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