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Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human
Quan Wen1, Huandi Weng1, Tao Liu1
1Guangdong-Hongkong-Macau Institute of CNS Regeneration, Ministry of Education CNS Regeneration Collaborative Joint Laboratory, Jinan University, Guangzhou 510632, P. R. China.
Abstract:
Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural development, including cilia organization, neuron migration and axon navigation. Here, we address its role in axon regeneration. We show that Celsr2 is highly expressed in both mouse and human spinal motor neurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones, with increased expression of end-binding protein 3 and higher potassium-induced calcium influx. Mice with Celsr2 conditional knockout in spinal motor neurons do not exhibit any behavioural deficits; however, after branchial plexus injury, axon regeneration and functional forelimb locomotor recovery are significantly improved. Similarly, knockdown of CELSR2 using shRNA interference in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motor neurons, Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun. In conclusion, Celsr2 negatively regulates motor axon regeneration and is a potential target to improve neural repair.
Insights
Scientists discovered that reducing Celsr2 levels enhances motor axon regeneration and functional recovery after injury. This finding identifies Celsr2 as a key target for improving neural repair strategies.
Area of Science:
- Neuroscience
- Cell Biology
- Regenerative Medicine
Background:
- Atypical cadherin Celsr2 is crucial for neural development, affecting cilia organization, neuron migration, and axon navigation.
- Understanding novel modulators of axon regeneration is vital for advancing neural repair therapies.
Purpose of the Study:
- To investigate the role of Celsr2 in motor axon regeneration and its potential as a therapeutic target.
- To determine if Celsr2 modulates axon regeneration in both mouse and human motor neurons.
Main Methods:
- Analysis of Celsr2 expression in mouse and human spinal motor neurons.
- Assessment of axon regeneration and fasciculation in Celsr2 knockout/mutant mouse models and cultured explants.
- Evaluation of neurite outgrowth, growth cone size, and molecular markers in Celsr2 mutant motor neurons.
- Investigation of functional recovery after branchial plexus injury in mice with conditional Celsr2 knockout.
- Examination of CELSR2 knockdown effects in human spinal motor neurons and explants.
- Measurement of signaling pathway components (Rac1, Cdc42, JNK, c-Jun) following Celsr2 downregulation.
Main Results:
- Celsr2 is highly expressed in spinal motor neurons.
- Celsr2 knockout or downregulation promotes axon regeneration, fasciculation, and neurite outgrowth in both mouse and human models.
- Celsr2 mutant motor neurons exhibit larger growth cones and increased calcium influx.
- Conditional Celsr2 knockout in mice improves functional recovery after nerve injury without behavioral deficits.
- Celsr2 downregulation correlates with increased activity of Rac1, Cdc42, JNK, and c-Jun signaling pathways.
Conclusions:
- Celsr2 acts as a negative regulator of motor axon regeneration.
- Downregulating Celsr2 enhances axonal regrowth and functional recovery, suggesting it is a promising therapeutic target for neural repair.
