{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nWNT8A has been implicated as a contributor to craniofacial development, with genetic variation in this gene associated with non‐syndromic cleft lip and/or palate. In one study, analysis of several Wnt family members in affected families revealed that single nucleotide polymorphisms in WNT8A, among other Wnt genes, were significantly associated with NSCLP, supporting its role in mid‐face formation and upper lip fusion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, WNT8A functions as an autocrine signaling ligand that initiates downstream pathways critical for organized tissue patterning. Upon binding to the receptor tyrosine kinase Ror2, WNT8A triggers planar cell polarity signaling that induces the formation of cytonemes—dynamic, actin‐based protrusions that transport WNT8A to neighboring cells. This cytoneme‐mediated transport enables precise paracrine activation of the β‐catenin pathway, promoting gene expression and cellular proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe broader significance of the Wnt pathway in craniofacial development further underlines the potential impact of WNT8A regulation. Studies on other Wnt family members have demonstrated that overall Wnt signaling is essential for proper facial process formation, suggesting that dysregulation of genes like WNT8A may contribute to developmental defects such as cleft lip and palate."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nInvestigations in human tumor cell lines have delineated differential expression patterns of WNT8A compared to its paralogue WNT8B. In these studies, WNT8A mRNA was undetectable in several pancreatic and brain tumor cell lines, whereas embryonal tumor lines expressed WNT8A and WNT8B in a coordinated manner. Moreover, modulation of differentiation or hormone signaling affected the expression levels of these genes, suggesting that WNT8A plays a role in the embryonal context, likely through synergistic activation of the β‐catenin–TCF transcriptional response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural insights into WNT8A have further advanced our understanding of its function at the molecular level. Cryogenic electron microscopy has revealed that palmitoleated WNT8A forms a complex with the dedicated transporter Wntless (WLS), which possesses a GPCR-like membrane domain. In this complex, a WNT hairpin of WNT8A inserts into a conserved hydrophobic cavity while its palmitoleate moiety interacts with the lipid bilayer—a configuration likely critical for its secretion and subsequent signaling function in body plan development and stem cell biology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLastly, genetic analyses in patients with Hirschsprung's disease have identified polymorphisms within WNT8A and observed increased mRNA and protein expression in stenotic colon segments. These findings indicate that aberrant WNT8A function may disturb normal enteric nervous system development, contributing to the pathogenesis of HSCR."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Brett T Chiquet, Susan H Blanton, Amber Burt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Variation in WNT genes is associated with non-syndromic cleft lip with or without cleft palate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddn121"}], "href": "https://doi.org/10.1093/hmg/ddn121"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18413325"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18413325"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Benjamin Mattes, Yonglong Dang, Gediminas Greicius, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.36953"}], "href": "https://doi.org/10.7554/eLife.36953"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30060804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30060804"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Renato Menezes, Ariadne Letra, Ana H Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Studies with Wnt genes and nonsyndromic cleft lip and palate."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Birth Defects Res A Clin Mol Teratol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/bdra.20720"}], "href": "https://doi.org/10.1002/bdra.20720"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20890934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20890934"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Tetsuroh Saitoh, Tetsuya Mine, Masaru Katoh "}, {"type": "b", "children": [{"type": "t", "text": "Expression and regulation of WNT8A and WNT8B mRNAs in human tumor cell lines: up-regulation of WNT8B mRNA by beta-estradiol in MCF-7 cells, and down-regulation of WNT8A and WNT8B mRNAs by retinoic acid in NT2 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11956596"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11956596"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rie Nygaard, Jia Yu, Jonathan Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2020.11.038"}], "href": "https://doi.org/10.1016/j.cell.2020.11.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33357447"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33357447"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Hong Gao, Dong Chen, Xiaomei Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymorphisms and expression of the WNT8A gene in Hirschsprung's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/ijmm.2013.1433"}], "href": "https://doi.org/10.3892/ijmm.2013.1433"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23836442"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23836442"}]}]}]}