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Associated Press
25-03-2025
- Health
- Associated Press
New genetic insights into hypospadias: MAFB and CEBPA's role in urothelial growth
GA, UNITED STATES, March 25, 2025 / / -- A recent study has unveiled the critical roles of two transcription factors, MAFB and CEBPA, in the development of hypospadias, a common congenital malformation affecting male urethral development. The research reveals that MAFB and CCAAT/enhancer-binding protein alpha (CEBPA) regulate urothelial cell growth via the Wnt/β-catenin signaling pathway, offering new insights into the genetic mechanisms underlying this condition. These findings pave the way for innovative therapeutic strategies and a deeper understanding of the genetic and molecular foundations of hypospadias. Hypospadias is characterized by an ectopic urethral opening and abnormal penile curvature, affecting approximately 1 in 200 live male births. While its origins are believed to stem from a combination of genetic and environmental factors, androgen signaling pathways are thought to play a significant role in the condition's development. Despite progress in identifying the genetic components, the precise molecular mechanisms remain poorly understood. Previous studies have suggested that the Wnt/β-catenin signaling pathway is involved in urethral development, but the specific contributions of transcription factors such as MAFB and CCAAT/enhancer-binding protein alpha (CEBPA) have yet to be fully explored. This gap in understanding highlights the need for in-depth research to elucidate the pathways involved in hypospadias. On September 13, 2024, a study (DOI: 10.1016/ published in Genes & Diseases and led by researchers from the Children's Hospital of Chongqing Medical University in China identified MAFB and CEBPA as crucial regulators of urothelial cell growth. By influencing cell proliferation and apoptosis through the Wnt/β-catenin signaling pathway, MAFB and CEBPA play a significant role in the genetic mechanisms of hypospadias. This research lays a strong foundation for future studies aimed at developing targeted therapies for this prevalent congenital condition. The study focused on the roles of MAFB and CEBPA in urothelial cell growth, utilizing human foreskin samples and mouse models. The researchers found that expression levels of MAFB and CEBPA were significantly reduced in the foreskin tissues of hypospadias patients. Using RNA sequencing and Western blot analysis, they discovered that MAFB knockdown led to suppressed CEBPA protein expression, inhibiting the Wnt/β-catenin pathway and causing cell cycle arrest and increased apoptosis in urothelial cells. Furthermore, MAFB overexpression promoted cell proliferation and activated the Wnt/β-catenin pathway, while CEBPA knockdown reversed these effects. These findings highlight the pivotal role of the MAFB-CEBPA axis in regulating urothelial cell growth and suggest that disruptions in this pathway may contribute to hypospadias development. The study also pinpointed potential therapeutic targets for future interventions. Dr. Xing Liu, the corresponding author of the study, commented, 'Our findings provide a deeper understanding of the molecular mechanisms underlying hypospadias. By identifying the roles of MAFB and CEBPA in urothelial growth, we have uncovered potential targets for therapeutic intervention, which could lead to improved outcomes for patients with this condition.' The discovery of the MAFB-CEBPA regulatory pathway holds immense potential for advancing the treatment and prevention of hypospadias. By targeting this pathway, researchers could develop novel therapies to correct or prevent the malformation during early development. Additionally, the study opens exciting new avenues for exploring the genetic and molecular underpinnings of other congenital disorders related to urethral development. Future research may focus on identifying additional genetic factors and environmental influences that interact with the MAFB-CEBPA pathway, further advancing our understanding of hypospadias and related conditions. DOI 10.1016/ Original Source URL Funding information This work was financed by the National Natural Science Foundation of China (No. 81970571), the Natural Science Foundation of Chongqing Municipality, China (No. CSTB2022NSCQ-MSX1001), and the Program for Youth Innovation in Future Medicine, Chongqing Medical University (No. W0109). Lucy Wang Legal Disclaimer:
Associated Press
18-03-2025
- Health
- Associated Press
New insights into hypospadias: SOX9's role in urethral formation revealed
GA, UNITED STATES, March 18, 2025 / / -- A recent study has uncovered the pivotal role of the transcription factor SOX9 in the development of hypospadias, a common congenital condition that affects male children. The research highlights how SOX9 regulates critical molecular pathways involved in urethral development, including the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT). The study reveals that reduced SOX9 expression leads to impaired EMT and abnormal Wnt signaling in tissues affected by hypospadias. These findings provide new insights into the condition's molecular underpinnings, potentially paving the way for innovative, targeted therapies. Hypospadias is a widespread congenital disorder, characterized by an abnormal placement of the urethral opening, impacting as many as 3.42% of male children worldwide. Beyond the physical consequences, this condition can lead to psychological and fertility issues. Surgical repair remains the only current treatment, but complications are common, and the genetic and cellular mechanisms involved remain poorly understood. With the prevalence of hypospadias on the rise, coupled with the challenges of surgical treatment, a deeper understanding of its molecular causes is urgently needed. Published (DOI: 10.1002/pdi3.94) on May 14, 2024, in Pediatric Discovery, the study conducted by researchers from the Children's Hospital of Chongqing Medical University delves into the role of SOX9 in the development of hypospadias. The study investigates the expression of SOX9 in foreskin tissues from hypospadias patients, focusing on its influence on the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT). The research team analyzed foreskin samples from 15 children with hypospadias, comparing them with normal foreskin tissues from children undergoing circumcision. Using molecular techniques such as transcription-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence, the researchers found that SOX9 expression was notably downregulated in hypospadias tissues. This downregulation was linked to reduced expression of key components of the Wnt/β-catenin pathway, including Wnt3a, LEF1, and GSK3β. Additionally, mesenchymal markers like Vimentin and α-SMA were also diminished, while epithelial markers such as E-cadherin, Occludin, and ZO-1 were elevated, suggesting a disrupted EMT process. Inhibition of SOX9 in foreskin fibroblasts replicated these effects, further confirming SOX9's crucial role in regulating Wnt/β-catenin signaling and EMT during urethral development. Dr. Xing Liu, the lead researcher, stressed the significance of the findings: 'This is the first study to pinpoint SOX9 as a key player in hypospadias development. By understanding how SOX9 governs Wnt/β-catenin signaling and EMT, we can identify potential new therapeutic strategies to treat this condition.' The implications of these findings extend beyond basic science, with significant potential for clinical application. By elucidating the molecular mechanisms of hypospadias, the study uncovers new therapeutic targets that could lead to non-surgical treatments. Additionally, these insights into the genetic basis of the condition could improve surgical outcomes, offering better predictions and tailored approaches. The research also opens up new possibilities for early diagnosis and intervention, which could help mitigate the psychological and fertility-related challenges faced by affected individuals. DOI 10.1002/pdi3.94 Original Source URL Funding information This work was financed by the National Natural Science Foundation of China (81970571), Natural Science Foundation Project of Science and Technology Commission of Chongqing (2022NSCQ-MSX0328) and Chongqing Medical University Program for Youth Innovation in Future Medicine. Lucy Wang BioDesign Research
