{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CELF4 is a neuron‐enriched RNA‐binding protein that plays a vital role in post‐transcriptional gene regulation by influencing alternative splicing, mRNA stability, and translation in the central nervous system. Its binding activity—largely focused on 3′ untranslated regions of a broad set of target transcripts—helps control the abundance and availability of messages that are critical for proper neuronal development and synaptic function (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Mouse models with CELF4 deficiency exhibit altered excitatory neurotransmission leading to complex seizure phenotypes, signifying its importance for maintaining the balance of neuronal excitability (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural analyses have delineated specific RNA recognition motifs in CELF4 that are required for its splicing activation functions, thereby clarifying its direct involvement in regulating alternative exon inclusion (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its neural roles, genetic variation in CELF4 has been implicated in modifying disease risk in other tissues. For instance, a single‐nucleotide polymorphism in CELF4 underlies a gene–environment interaction that markedly increases the risk of anthracycline-associated cardiomyopathy by altering the splicing of cardiac troponin T (TNNT2) (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In another disease context, a rare intronic variant in CELF4 is associated with an increased risk of colorectal cancer, revealing a potential wider impact of CELF4 in oncogenesis (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, reduced expression of CELF4 in the prefrontal cortex—accompanied by a loss of dendritic spines—has been linked with depression-like behaviors in mice, indicating that CELF4 levels may also influence mood regulation (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Finally, developmental studies have demonstrated that CELF4 is expressed in differentiating neuronal populations of the retina, suggesting that its regulatory functions extend into broader aspects of neurodevelopment (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, a convergence of evidence shows that CELF4 is a multifaceted regulator of RNA processing in neurons whose activity is essential for proper excitatory neurotransmission and synaptic plasticity. Its dysregulation—whether through functional deficiency or genetic variation—not only contributes to neurological disorders such as epilepsy and autism spectrum disorders but also influences susceptibility to cardiomyopathy and colorectal cancer. These findings underscore the clinical and biological significance of CELF4 across diverse tissues (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "1"}, {"type": "fg_fs", "start_ref": "3", "end_ref": "7"}, {"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jacy L Wagnon, Michael Briese, Wenzhi Sun, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CELF4 regulates translation and local abundance of a vast set of mRNAs, including genes associated with regulation of synaptic function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1003067"}], "href": "https://doi.org/10.1371/journal.pgen.1003067"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23209433"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23209433"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sahar Gelfman, Quanli Wang, Yi-Fan Lu, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "ETR-3 and CELF4 protein domains required for RNA binding and splicing activity in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nucleic Acids Res (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/nar/gkh275"}], "href": "https://doi.org/10.1093/nar/gkh275"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14973222"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14973222"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Xuexia Wang, Can-Lan Sun, Adolfo Quiñones-Lombraña, et al. 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