Neurochemistry international · 2026
F-box and WD repeat domain-containing 7 promotes nerve regeneration to exert therapeutic protection against preterm brain injury by degrading Notch receptor 1.
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Chang Shuting, Huang Weiqing, Yi Biao, Fu Chenchao
Аннотация
BACKGROUND: Preterm brain injury (PBI) can lead to severe neurodevelopmental impairment. F-box and WD repeat domain-containing 7 (FBXW7) is a key regulator of neural development. This study evaluated the effect of FBXW7 on nerve regeneration after PBI.
METHODS: A mouse model of PBI and an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) in neural stem cells (NSCs) were established. Cognitive and motor functions were assessed using Morris water maze, wire hanging, and cylinder tests. Histopathological changes and apoptosis were evaluated by hematoxylin and eosin and TdT-mediated dUTP Nick-End Labeling, and immunohistochemical staining for myelin basic protein and microtubule-associated protein 2 (MAP2). Neuroregeneration was analyzed via immunofluorescence (IF) staining for bromodeoxyuridine, doublecortin, and MAP2. FBXW7 and Notch receptor 1 (Notch1) expressions were detected by real-time quantitative PCR and Western blot. The viability, apoptosis and differentiation of NSCs were measured by cell counting kit-8, flow cytometry, and IF/Western blot. Protein interaction, stability, and ubiquitination were examined by co-immunoprecipitation and cycloheximide chase assays.
RESULTS: FBXW7 expression was decreased in PBI mice and OGD/R-treated NSCs. Overexpression of FBXW7 significantly alleviated the pathological damage and behavioral impairments after PBI, and also enhanced the nerve regeneration process. Moreover, FBXW7 not only enhanced NSCs survival and suppressed apoptosis following OGD/R, but also actively drove their differentiation toward a neuronal lineage. Mechanistically, FBXW7 promoted the ubiquitination and degradation of Notch1. FBXW7 induced NSCs differentiation following OGD/R and mediated neuroprotection to protect PBI by inhibiting Notch1 signaling.
CONCLUSION: By enhancing neuroregeneration via degradation of Notch1, FBXW7 appears to play a protective role in PBI, which suggests therapeutic targets for PBI treatment that merit further exploration.
METHODS: A mouse model of PBI and an in vitro model of oxygen-glucose deprivation/reperfusion (OGD/R) in neural stem cells (NSCs) were established. Cognitive and motor functions were assessed using Morris water maze, wire hanging, and cylinder tests. Histopathological changes and apoptosis were evaluated by hematoxylin and eosin and TdT-mediated dUTP Nick-End Labeling, and immunohistochemical staining for myelin basic protein and microtubule-associated protein 2 (MAP2). Neuroregeneration was analyzed via immunofluorescence (IF) staining for bromodeoxyuridine, doublecortin, and MAP2. FBXW7 and Notch receptor 1 (Notch1) expressions were detected by real-time quantitative PCR and Western blot. The viability, apoptosis and differentiation of NSCs were measured by cell counting kit-8, flow cytometry, and IF/Western blot. Protein interaction, stability, and ubiquitination were examined by co-immunoprecipitation and cycloheximide chase assays.
RESULTS: FBXW7 expression was decreased in PBI mice and OGD/R-treated NSCs. Overexpression of FBXW7 significantly alleviated the pathological damage and behavioral impairments after PBI, and also enhanced the nerve regeneration process. Moreover, FBXW7 not only enhanced NSCs survival and suppressed apoptosis following OGD/R, but also actively drove their differentiation toward a neuronal lineage. Mechanistically, FBXW7 promoted the ubiquitination and degradation of Notch1. FBXW7 induced NSCs differentiation following OGD/R and mediated neuroprotection to protect PBI by inhibiting Notch1 signaling.
CONCLUSION: By enhancing neuroregeneration via degradation of Notch1, FBXW7 appears to play a protective role in PBI, which suggests therapeutic targets for PBI treatment that merit further exploration.