{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPAX6 is a quintessential master regulator that orchestrates early neuroectoderm and ocular development. In human embryos and stem‐cell–derived neuroectoderm, PAX6 is uniformly expressed and acts as a transcriptional determinant that drives the transition from pluripotency to neural fate, while its dosage and autoregulatory mechanisms finely tune the spatial and temporal expression patterns critical for proper brain regionalization, lens induction, and retinal differentiation. PAX6 furthermore plays indispensable roles in the patterning of neural progenitors and the establishment of neurogenic niches, and its mutations underline structural brain anomalies as well as classic ocular malformations such as aniridia and coloboma. These central functions have been elucidated by studies demonstrating its binding to key gene promoters and integration of extracellular signals to activate tissue‐specific differentiation programs."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn ocular tissues, PAX6 additionally governs cell‐fate decisions that specify the retinal lineage and the identity of the corneal epithelium and its stem cell compartment. In paradigms of corneal differentiation and limbal stem cell maintenance, PAX6 cooperates with other transcription factors and signaling pathways (including WNT, TGF‑β and FGF) to direct differentiation toward ocular surface fates, while its dysregulation or loss causes a fate shift toward skin-like epithelium and contributes to disorders such as aniridia and myopia. Moreover, specific isoforms of PAX6—such as the Pax6(+5a) variant—exhibit distinct DNA-binding properties that, upon ectopic expression, can induce a retina-like architecture or mediate transdifferentiation of retinal pigment epithelial cells, underscoring its potent instructive capacity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its well‐established roles in the central nervous system and eye, PAX6’s transcriptional networks extend to endocrine tissues and cancer. In pancreatic islet cells, for instance, PAX6 maintains β‑cell identity by activating genes required for insulin production while repressing alternative islet hormones, and in α‑cells it cooperates with partners such as c‑Maf to fine-tune glucagon gene transcription. Moreover, interactions between distinct PAX6 isoforms and posttranslational modifications (for example, HIPK2-mediated phosphorylation) enhance its transcriptional activity, while multidomain dynamics ensure efficient promoter targeting. Intriguingly, altered PAX6 expression—whether via mutations, aberrant methylation, or dysregulated enhancer activity—has been implicated in tumorigenesis in gliomas and pancreatic carcinomas, highlighting its broad impact on cell fate and maintenance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "38", "end_ref": "49"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Caroline Griffin, Dirk A Kleinjan, Brendan Doe, et al. 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