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).
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.
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.
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.
Journal of pediatric urology. 2024 Oct 05 [Epub ahead of print]
Boyu Xie, Michael Millar, Callum Arthurs, Navroop Johal, Christopher Fry, Aamir Ahmed
Centre for Gene Therapy and Regenerative Medicine, Guy's Hospital, Great Maze Pond, King's College London, London SE1 9RT, UK., Institute for Regeneration and Repair, University of Edinburgh, Edinburgh EH16 4UU, UK., Department of Urology, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK., School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol BS8 1TD, UK., Centre for Gene Therapy and Regenerative Medicine, Guy's Hospital, Great Maze Pond, King's College London, London SE1 9RT, UK; Department of Cell and Developmental Biology, Rockefeller Building, University Street, University College London, London WC1E 6JJ, UK. Electronic address: .