{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Capicua (CIC) is a conserved high‐mobility group box transcriptional repressor that plays multifaceted roles in normal development and disease. In the central nervous system, CIC represses target genes—including members of the PEA3 (ETV) family—to regulate neuronal differentiation and proper lineage progression, as shown by its requirement for hippocampal neurogenesis through interactions with SIN3‐HDAC and BRG1‐containing mSWI/SNF complexes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In parallel, in models of spinocerebellar ataxia type 1 (SCA1) the pathological gain‐of‐function of the ATXN1–CIC complex drives Purkinje cell dysfunction and accelerates cerebellar degeneration, whereas disruption of the complex mitigates disease features."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": " Moreover, CIC activity is tuned by upstream ERK signaling: ERK‐mediated phosphorylations modulate CIC’s subcellular localization and DNA‐binding affinity, thereby controlling the expression of its downstream effector genes such as ETV1, ETV4, and ETV5, which in turn influence processes including cell migration and resistance to pathway inhibitors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of tumorigenesis, CIC has emerged as a key tumor suppressor. In oligodendroglial tumors, for example, recurrent mutations and deletions in CIC are frequent and are implicated in the distinct gene expression patterns and better prognostic profiles observed in these cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Additionally, loss of CIC function has been linked to resistance against MAPK pathway inhibitors in several cancer models, underscoring its role in mediating cellular responses to external growth signals."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies position CIC as a central regulator whose normal activity is critical for neuronal development, while its mutation or altered expression contributes to both neurodegenerative conditions such as SCA1 and various malignancies. Whether by directly modulating gene transcription in response to extracellular cues or through its integration in multiprotein complexes that determine cell fate and survival, CIC represents a nexus point linking developmental signaling and disease pathogenesis.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Inah Hwang, Heng Pan, Jun Yao, et al. 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