{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNeurotrophin‐4 (NTF4/NT‐4) is emerging as a multifunctional signaling molecule with diverse roles in neural survival, development, and beyond. In the nervous system, NT‐4 is critical for maintaining neuronal viability, particularly in retinal ganglion cells where mutations in the NTF4 gene have been implicated in primary open‐angle glaucoma by reducing TrkB receptor activation. Indeed, functional studies demonstrate that NTF4 mutations lead to impaired neurotrophic signaling and compromised retinal support, a finding further supported by investigations in different populations and animal models. Moreover, correlations between NT‐4 levels and long‐chain polyunsaturated fatty acids in amniotic fluid point to a role in fetal brain neurogenesis, while NT‐4–TrkB signaling has been shown to confer neuroprotection following neonatal brain injury."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDistinct intracellular trafficking mechanisms also contribute to NT‐4’s functional specificity. For example, while alterations in the sorting protein sortilin lead to missorting and defective release of brain‐derived neurotrophic factor (BDNF), NT‐4 secretion remains unaffected—suggesting that NT‐4 employs divergent pathways for regulated exocytosis. In parallel, NT‐4 has been shown to promote cell migration in melanoma cell lines, thereby modulating tumor cell motility and potentially affecting metastatic behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in neuronal and tumor cell dynamics, NT‐4 influences immune and inflammatory processes. Studies in allergic asthma have demonstrated that NT‐4 enhances the viability and activation marker expression of eosinophils in bronchoalveolar lavage fluid, thereby contributing to local inflammation. Additionally, in mastocytosis, elevated serum NT‐4 levels correlate with mast cell load, suggesting that NT‐4, acting through its receptors, may promote mast cell differentiation and migration via autocrine/paracrine loops."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn reproductive and developmental contexts, NT‐4 is widely expressed in ovarian and dental tissues. Immunohistochemical and transcript analyses reveal NT‐4/5 expression in oocytes, granulosa cells, and dental epithelia—a pattern that implicates NT‐4 in primordial follicle assembly, germ cell survival, and tooth morphogenesis. Its regulatory influence extends to in vitro studies where NT‐4 modulates follicular assembly in human fetal ovaries and supports the growth of preantral follicles. Moreover, NT‐4 contributes to the regulation of human periodontal ligament cell proliferation and differentiation, underscoring a role in tissue regeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNT‐4 also modulates pulmonary function. In airway smooth muscle cells, NT‐4 exerts a modest influence on calcium signaling compared with BDNF, indicating a nuanced role in regulating bronchial contractility. In contrast, within the context of pulmonary fibrosis, dysregulation of the TrkB/NT‐4 axis has been linked to enhanced proliferation of alveolar type II cells and fibroblasts, suggesting that NT‐4 signaling might contribute to the fibrotic remodeling process."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in NT‐4 levels have been associated with psychiatric conditions as well. Elevated circulating NT‐4 levels have been reported in bipolar disorder patients across different mood states—hinting at a compensatory or state‐dependent neurotrophic response. However, meta‐analyses of exercise interventions reveal heterogeneous and sometimes contradictory changes in NT‐4/5 levels in animal models, highlighting the complexity of its systemic regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, NT‐4 plays a role in cancer progression. Overexpression of NTF4 has been implicated as a novel oncogenic driver in colorectal cancer, where it suppresses autophagy to promote cell invasion, proliferation, and migration. Similarly, altered NT‐4 expression in gastric cancer suggests potential diagnostic and prognostic utility, while its influence on periodontal ligament cell differentiation may further intersect with oncogenic pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}, {"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Francesca Pasutto, Tomoya Matsumoto, Christian Y Mardin, et al. 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