{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeuregulin 3 (NRG3) is a critical member of the neuregulin family that serves as a high‐affinity, neural‐enriched ligand for the ErbB4 receptor. It plays multiple roles in neurodevelopment and central nervous system function by promoting neuronal differentiation, synaptic formation, and oligodendrocyte survival. Alternative splicing gives rise to several structurally distinct isoforms with tightly regulated temporal and spatial expression patterns, and genetic variations in NRG3 have been implicated in psychiatric disorders such as schizophrenia, bipolar disorder, attention‐deficit/hyperactivity disorder, and associated cognitive impairments. In particular, several studies report that risk‐associated single-nucleotide polymorphisms in NRG3 are linked to abnormalities in prefrontal cortical activation, early attentional processes, and increased severity of psychotic symptoms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in brain development and psychiatric traits, NRG3 also contributes to peripheral developmental processes and disease. In the embryo, an NRG3 isoform acts as a specification signal during mammary placode formation through activation of ErbB4, thereby regulating cell proliferation and differentiation. Structural variations and copy number changes in NRG3 have been associated with disorders of the enteric nervous system such as Hirschsprung disease, reinforcing its developmental importance outside the central nervous system. Moreover, in the oncological arena, aberrant transcriptional activation of NRG3 (for example, when complexed with the transcription factor WSTF in KRAS mutant colon tumors) appears to propagate oncogenic signals to neighboring cells. NRG3 is also regulated by environmental stressors; chronic nicotine exposure and subsequent withdrawal have been shown to increase its mRNA and protein expression, a modulation that contributes to nicotine dependence by impacting anxiety-related behaviors."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, NRG3 is synthesized as a membrane‐bound precursor that undergoes regulated post‐translational processing. Proteolytic cleavage—mediated by BACE1 within the trans-Golgi network—releases a mature ligand that is then incorporated into the somatodendritic membrane, re-endocytosed, and sorted into axonal carriers via Rab4-positive vesicles. This transcytotic mechanism, in combination with a “trans-synaptic retention” process wherein presynaptic accumulation is mediated through stable interactions with postsynaptic ErbB4 receptors, is essential for fine-tuning synaptic signaling and neural connectivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christelle Carteron, Antonio Ferrer-Montiel, Hugo Cabedo "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of a neural-specific splicing form of the human neuregulin 3 gene involved in oligodendrocyte survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.02799"}], "href": "https://doi.org/10.1242/jcs.02799"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16478787"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16478787"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Edmund J S Sonuga-Barke, Jessica Lasky-Su, Benjamin M Neale, et al. 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