{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSIX3 is a critical homeobox‐containing transcription factor that orchestrates early vertebrate organogenesis. It regulates the balance between cell proliferation and differentiation in the developing retina by antagonizing factors such as geminin, and it directly activates enhancers of key signaling molecules such as Sonic hedgehog (SHH) in the forebrain. Mutations in SIX3 have been repeatedly linked to midline defects including holoprosencephaly, schizencephaly, and other forms of congenital malformations affecting the forebrain, eyes, and pituitary. In genetically heterogeneous cases, both loss‐of‐function mutations and inherited deletions of SIX3 cause variable phenotypes with incomplete penetrance, highlighting its dosage‐dependent role in early neural and ocular development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in congenital malformations, SIX3 modulates neural progenitor cell behavior. In the developing telencephalon, ectopic expression of SIX3 accelerates cell cycle exit and enhances clonal expansion, thereby maintaining neural precursors in an undifferentiated state. In the retina, SIX3 interacts with chromatin modifiers such as MTA1 to regulate the transcription of key genes (for example, rhodopsin), underscoring its function in fine‐tuning the gene networks that control neural and sensory cell fate decisions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSIX3 is also increasingly recognized for its context‐dependent roles in human cancers. In some tumors—such as glioma and astrocytoma—epigenetic silencing of SIX3 via promoter hypermethylation is associated with enhanced cell cycle progression, invasion, and tumorigenesis, suggesting a tumor‐suppressive function. In contrast, in lung adenocarcinoma, esophageal cancer, and head and neck carcinomas, SIX3 can be overexpressed or deregulated through mechanisms that involve post‐translational degradation (for example, via the E3 ubiquitin ligase TRIM27) or modulation by microRNAs (e.g. miR-4306). In these settings, SIX3 influences key signaling pathways such as Wnt/β‐catenin and PI3K/Akt, and its interactions with cofactors like NOR-1 further modulate transcriptional outputs that control proliferation, migration, and metastasis. Together, these studies indicate that SIX3 can function either as a tumor suppressor or an oncogenic modifier, with its net effect determined by the affected tissue type and the upstream regulatory context."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Filippo Del Bene, Kristin Tessmar-Raible, Joachim Wittbrodt "}, {"type": "b", "children": [{"type": "t", "text": "Direct interaction of geminin and Six3 in eye development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature02292"}], "href": "https://doi.org/10.1038/nature02292"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14973488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14973488"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yongsu Jeong, Federico Coluccio Leskow, Kenia El-Jaick, et al. 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