{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FLRT3 is a fibronectin leucine‐rich transmembrane protein that plays pleiotropic roles during development and in the adult. In the nervous system, FLRT3 functions as an endogenous postsynaptic ligand for latrophilin receptors, where its high‐affinity binding is essential for the formation and maintenance of excitatory (glutamatergic) synapses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Structural studies have revealed that FLRT3 binds latrophilin3 at a distinct site and can simultaneously recruit other receptors such as UNC5, suggesting that FLRT3 contributes to the organization of trans‐synaptic complexes that regulate synapse development and stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its synaptic functions, FLRT3 is expressed dynamically during embryogenesis. Its regulated expression in migrating neuronal populations—as seen in the cortex, thalamocortical regions, and craniofacial structures—indicates that FLRT3 modulates intercellular adhesion and influences cell migration. For instance, loss of FLRT-mediated adhesion is associated with enhanced neuronal migration and even cortical folding, underscoring its role as a “molecular glue” in maintaining tissue organization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, in thalamocortical axon guidance, FLRT3 serves as a novel co‐receptor with Robo1 to modulate the response to the attractive cue Netrin‐1, thereby fine‐tuning axonal trajectories."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n FLRT3 is also implicated in the modulation of fibroblast growth factor (FGF) signaling during embryonic development. Its expression in regions such as the developing somite and the apical ectodermal ridge suggests that, by interacting with FGFR1, FLRT3 can regulate aspects of cell migration and differentiation in various organ systems."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n In the developing heart, for example, FLRT3—functionally interchangeable with its family member FLRT2—contributes to proper epicardial development, illustrating its importance in coordinated tissue morphogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in development, FLRT3 has been linked to disease. In cancer cells, elevated levels of FLRT3 have been observed in conjunction with latrophilin isoforms, where FLRT3 appears to participate in pathways that protect tumor cells from immune‐mediated cytotoxicity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " In addition, emerging genetic evidence points to variants in FLRT3 as candidate risk factors in disorders such as high myopia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Thus, FLRT3 functions as a versatile mediator of cell–cell adhesion and signaling. Its ability to interact with different receptor partners—in synapse formation, axon guidance, and FGF signaling modulation—illustrates how FLRT3 contributes to the precise control of tissue patterning and neural circuit assembly during development as well as to pathological processes when its regulation is disrupted.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Matthew L O'Sullivan, Joris de Wit, Jeffrey N Savas, et al. 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