{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Cytokine receptor‐like factor 3 (CRLF3) has emerged as a multifunctional protein with roles in diverse biological contexts. Reduced CRLF3 expression in human induced pluripotent stem cell–derived forebrain organoids from NF1 patients has been linked to deficits in neuronal differentiation, survival, and maturation that are accompanied by impaired RhoA signaling and an increased burden of autistic traits."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the murine system, CRLF3 deficiency specifically disrupts the later stages of platelet production by impairing preplatelet maturation—an effect associated with increased microtubule stability and altered Hippo pathway activity—resulting in a sustained reduction in circulating platelet numbers."}, {"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, unbiased biomarker discovery in Alzheimer’s disease has identified CRLF3 as part of an optimum gene set capable of discriminating patients from controls, pointing to its potential utility as a diagnostic marker in neurodegenerative conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, genome-wide association studies in chickens implicate CRLF3 in adaptive immune responses, suggesting a role in modulating the host’s immune reactivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Complementary functional genomic approaches further support a role for CRLF3 in the nervous system. A morphology-based gene trap screen in PC12 cells identified Crlf3 as a regulator of neuronal shape and synaptic vesicle transport"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while cellular studies in 293T cells have demonstrated that overexpressed CRLF3 localizes to both the cytoplasm and the cell membrane."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, inducible RNA interference using a tetracycline-regulated system in K562 cells has been successfully employed to modulate CRLF3 expression, thereby validating it as a candidate for functional perturbation studies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Upregulation of CRLF3 in cutaneous squamous cell carcinoma suggests that it may also play a role in cell cycle regulation or tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, evolutionary and comparative studies underscore the conserved nature of CRLF3 across eumetazoans. In both invertebrate and vertebrate models, CRLF3 functions as an orphan receptor that may mediate neuroprotective signaling in response to erythropoietin or related ligands, thereby contributing to tissue protection and survival under stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, CRLF3 appears to be a versatile protein that regulates critical aspects of neuronal development and neuroprotection, plays an important role in platelet maturation, and may contribute to immune modulation and oncogenesis. Its evolutionary conservation further highlights its potential as a target for therapeutic intervention in diverse pathophysiological conditions.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michelle L Wegscheid, Corina Anastasaki, Kelly A Hartigan, et al. 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