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Войти в исследования CNS neuroscience & therapeutics · 2026
TTBK2-Driven Ciliogenesis Is Required for Intrinsic Neuronal Regeneration After Spinal Cord Injury.
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Zhang Renfeng, Pan Su, Tian Zhenwei, Du Haorui, Wang Jintao, Yang Xiaoyu, Qi Zhiping
Аннотация
BACKGROUND: The primary cilium (PC) is a pivotal organelle for neuronal signaling and development, while tau tubulin kinase 2 (TTBK2) is a key initiator of ciliogenesis. However, the role of TTBK2 in spinal neurons during spinal cord injury (SCI) and subsequent neural repair remains unclear.
METHODS: We manipulated TTBK2 expression in spinal neurons using adenovirus-mediated overexpression and knockdown in vitro. Transcriptomic profiling (RNA-sequencing) and RT-qPCR were employed to explore the potential regulatory pathways at the molecular level. In vivo, Ttbk2fl/fl-Rosa-CreERT2+/- conditional knockout mice were subjected to a spinal cord hemisection model. Behavioral assays, immunofluorescence, and biotinylated dextran amine (BDA) tracing were conducted to assess neuronal survival, axonal regeneration, and circuit reorganization.
RESULTS: Here, we demonstrated that intact activity of TTBK2 in PC promoted neural survival, axonal regeneration, and neural circuit remodeling. However, loss of TTBK2 impaired PC function and hindered recovery after SCI.
CONCLUSIONS: These findings extend the role of PCs beyond neurodevelopment, demonstrating that the TTBK2-PC functions as an endogenous repair mechanism after SCI. Targeting this pathway may provide novel therapeutic strategies for enhancing neural regeneration.
METHODS: We manipulated TTBK2 expression in spinal neurons using adenovirus-mediated overexpression and knockdown in vitro. Transcriptomic profiling (RNA-sequencing) and RT-qPCR were employed to explore the potential regulatory pathways at the molecular level. In vivo, Ttbk2fl/fl-Rosa-CreERT2+/- conditional knockout mice were subjected to a spinal cord hemisection model. Behavioral assays, immunofluorescence, and biotinylated dextran amine (BDA) tracing were conducted to assess neuronal survival, axonal regeneration, and circuit reorganization.
RESULTS: Here, we demonstrated that intact activity of TTBK2 in PC promoted neural survival, axonal regeneration, and neural circuit remodeling. However, loss of TTBK2 impaired PC function and hindered recovery after SCI.
CONCLUSIONS: These findings extend the role of PCs beyond neurodevelopment, demonstrating that the TTBK2-PC functions as an endogenous repair mechanism after SCI. Targeting this pathway may provide novel therapeutic strategies for enhancing neural regeneration.