{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWNT7A is a multifunctional secreted glycoprotein that plays a pivotal role in normal embryonic development and adult tissue regeneration. In mesenchymal progenitor cells, it is regulated by MAP kinase cascades during chondrogenesis, underscoring its importance in cartilage‐specific differentiation and cell–cell adhesion events."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the ocular system, WNT7A couples with the transcription factor PAX6 to govern corneal epithelial cell fate, ensuring proper differentiation and wound repair."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Its critical function in limb development is highlighted by the discovery that missense and null mutations in WNT7A cause Fuhrmann syndrome and phocomelia, reflecting its role in dorsoventral patterning."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In addition, WNT7A is essential for postmenstrual endometrial re‐epithelialization"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", participates in the regulation of neural stem cell self‐renewal in the olfactory bulb"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and promotes osteoblast differentiation from mesenchymal stem cells by upregulating RUNX2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, despite investigations into Müllerian duct anomalies that did not identify causal mutations in WNT7A"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", its fundamental role in developmental processes remains unequivocal.\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer, WNT7A exhibits context‐dependent functions that range from tumor suppression to oncogenic promotion. In non‐small cell lung cancer, re‐expression of WNT7A reactivates beta‐catenin–dependent signaling to induce E‐cadherin expression and promote epithelial differentiation, thereby counteracting malignant transformation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Moreover, signaling via the WNT7A/Frizzled9 axis activates peroxisome proliferator‐activated receptor gamma (PPARγ), further contributing to its tumor‐suppressive properties"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Conversely, in ovarian carcinoma, elevated WNT7A expression has been linked to enhanced beta‐catenin/TCF signaling and increased invasiveness"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", a scenario paralleled in endometrial cancer where WNT7A overexpression correlates with disease progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "and in tongue squamous cell carcinoma where it promotes epithelial–mesenchymal transition (EMT) and tumor aggressiveness."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Epigenetic silencing via promoter hypermethylation contributes to the loss of WNT7A expression in renal cell carcinoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", while microRNA‐mediated regulation – for example, by miR‑370‑3p – further modulates its expression and influences invasive behavior in bladder cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Additional studies have reported similar oncogenic roles in esophageal carcinoma through circRNA‐mediated upregulation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", in endometrial malignancies"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", and in ovarian cancer where high WNT7A levels predict poor prognosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " In tongue squamous cell carcinoma and glioma, aberrant WNT7A signaling fosters EMT and metastatic progression"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ";"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", while modulation of receptor interactions further supports its complex role in lung cancer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its developmental and oncogenic roles, WNT7A orchestrates diverse signaling cascades that fine‐tune cellular responses. It modulates chondrocyte dedifferentiation and survival in arthritic cartilage by engaging both canonical beta‐catenin and non‐canonical cell survival pathways"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": ", and through its partnership with Frizzled7, it enhances skeletal muscle satellite cell polarity and migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " In the cornea, WNT7A is rapidly induced following injury to activate beta‐catenin accumulation and Rac signaling, which in turn upregulates MMP‐12 and accelerates wound closure"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " Biochemical assays have confirmed that WNT7A binds with high affinity to Frizzled receptors via its cysteine‐rich domains, a process essential for activating downstream pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " Associations between genetic variations in WNT pathway components and neuroanatomical as well as mood disorder phenotypes further underscore its broad regulatory capacity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " Reviews of WNT signaling in limb patterning also highlight the unique dorsalizing activity of WNT7A."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Structural analyses have further detailed the mechanisms of WNT7A secretion, including its interactions with chaperones such as calreticulin and the regulatory influence of bound phospholipids"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": ", while investigations into pancreatic endocrine tumors have probed its inactivation, albeit without consistent biallelic loss."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": " In the context of reproductive biology, studies evaluating Müllerian duct anomalies did not implicate coding mutations in WNT7A"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": ", and emerging evidence in assisted reproductive technology indicates that microRNA alterations impacting WNT7A (and related WNT ligands) may serve as biomarkers for implantation success."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": " Furthermore, canonical WNT signaling (with potential contributions from WNT7A) is implicated in blood–brain barrier integrity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": ", while in immune cells, WNT7A modulates macrophage phenotype and cytokine production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Recent high‐resolution structural studies have provided additional insights into receptor engagement and secretion mechanisms for WNT7A"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": ", and changes in circulating microRNAs affecting WNT7A levels have been associated with successful embryo implantation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": " Moreover, although screening in congenital clubfoot has revealed only non‐causative promoter variants"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": ", these studies collectively emphasize that intricate regulatory processes governing WNT7A activity hold promise for future diagnostic and therapeutic strategies.\n"}]}, {"type": "t", "text": " \n\n<!-- Note: The citation numbering above reflects the sequential order in which the 38 provided PubMed abstracts have been integrated into this cohesive summary. 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