{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPAX2 is a critical developmental transcription factor that orchestrates kidney morphogenesis and urogenital system formation. It is fundamentally involved in the mesenchymal‐to‐epithelial transition necessary for nephron formation, as well as in patterning the developing renal and reproductive tracts. Mutations or haploinsufficiency of PAX2 lead to congenital anomalies such as renal hypodysplasia, renal–coloboma (papillorenal) syndrome, and subtle renal hypoplasia linked to reduced nephron number. In addition, studies in embryonic human tissues and induced pluripotent stem cells reveal that while PAX2 is essential for early renal progenitor specification, its activity must be precisely modulated to ensure proper epithelial differentiation of nephron components and differentiation of urogenital epithelia in both males and females."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of diagnostic pathology, PAX2 expression serves as a valuable immunohistochemical marker in renal neoplasms. Its re‐expression in renal cell carcinomas (especially clear cell and papillary subtypes) aids in distinguishing renal tumors from morphologic mimics. Although diagnostic panels often include a combination of markers such as PAX8, aquaporins, CD10, and RCC marker antibodies, PAX2 remains a component of these panels due to its frequent activation in lower-grade renal tumors and its utility in identifying metastatic disease. However, its sensitivity and specificity have to be interpreted in context, as expression levels vary among different tumor subtypes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental role, PAX2 mutations and aberrant expression are implicated in a spectrum of renal diseases and other neoplasms. Exome studies have revealed that PAX2 mutations contribute to familial forms of focal segmental glomerulosclerosis and congenital anomalies of the kidney and urinary tract. In parallel, loss of PAX2 expression (yielding “PAX2‐null” lesions) in the fallopian tube epithelium has been linked with benign outgrowths that may precede serous carcinoma, suggesting that both its gain and loss can be associated with pathogenesis. Moreover, genetic studies underscore its role in the interplay with tumor suppressors and other regulatory networks, such as p53, to determine final nephron endowment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPAX2 also contributes to tumorigenesis in nonrenal tissues. Studies indicate that in cancers such as melanoma, esophageal squamous cell carcinoma, prostate cancer, and certain ovarian neoplasms, aberrant PAX2 expression confers growth advantages, enhances cell survival, and modulates invasion through regulation of downstream targets (for example, ADAM10 or hBD1). Its transcriptional activity is fine‐tuned by interactions with cofactors like p300 and PTIP, and its expression in progenitor cell populations is regulated by specific microRNAs. These regulatory mechanisms underscore the potential of PAX2 as a therapeutic target to sensitize tumors to conventional treatments."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, broader applications of PAX2 as a biomarker extend to its use in differential diagnoses within the female genital tract and central nervous system, where its expression pattern helps distinguish developmental origins and neoplastic processes. For instance, absence of PAX2 expression in select endometrial and mesonephric lesions aids in the accurate classification of benign versus malignant entities. 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