Celsr2 Knockout Alleviates Inhibitory Synaptic Stripping and Benefits Motoneuron Survival and Axon Regeneration After Branchial Plexus Avulsion

Axotomy-induced synaptic stripping modulates survival and axon regeneration of injured motoneurons. Celsr2 is supposed to mediate homophilic interactions of neighboring cells during development, and its role in synaptic stripping remains unknow. In a model of brachial plexus avulsion, Celsr2 knockout improved functional recovery, motoneuron survival, and axon regeneration. Celsr2 was indicated to express in spinal motoneurons, excitatory and inhibitory interneurons, astrocytes, and a subset of oligodendrocytes using Celsr2(LacZ) mice. Double immunostaining showed that the coverage of inhibitory and excitatory vesicles on injured motoneurons were remarkably reduced after injury, whereas more inhibitory vesicles were maintained in Celsr2(−/−) mutants than control mice. In the ultrastructure, the density of inhibitory F-boutons on injured motoneurons was higher in Celsr2(−/−) mutants than controls. Conditional knockout of Celsr2 in astrocytes or oligodendrocytes showed the similar axotomy-induced synaptic withdrawal to the control. RNAseq of injured spinal samples identified 12 MHC I molecules with significant changes between Celsr2(−/−) and control mice. After injury, expression of MHC I surrounding injured motoneurons was increased, particularly high in Celsr2(−/−) mutants. In conclusion, Celsr2 knockout enhances MHC I signaling, alleviates inhibitory synaptic stripping cell-autonomously, and contributes to motoneuron survival and regeneration, and Celsr2 is a potential target for neural repair. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12035-022-03198-3.