Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human

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 motoneurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motoneurons 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 motoneurons do not exhibit any behavioral 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 motoneurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motoneurons, 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.

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

“…The decrease of reactive astrocytes in Celsr2 −/− injured spinal cords was mainly found at day 14 and 21 after BPA, and the direct effect of Celsr2 inactivation on astrocytes could not be excluded. In our study, Celsr2 −/− mice have better axon regeneration and functional recovery after BPA, and this outcome may attribute to two explanations: firstly, Celsr2 inactivation benefits neuronal survival through regulating synaptic stripping in the present work, which alleviates the excitotoxicity on injured motoneurons to facilitate their survival; secondly, Celsr2 inactivation elevates small GTPases in injured motoneurons to enhance their regeneration ability in the previous report [36,47].…”

“…In the ventral horn, motoneurons receive inhibitory and excitatory inputs from spinal segmental interneurons. Our previous studies showed that all spinal motoneurons were expressed by Celsr2 [ 36 ]. Using Celsr2 LacZ mice, in which Celsr2 expression could be visualized by β-gal signal, we found that Parvalbumin-positive, Calretinin-positive GABAergic, and CamKII-positive glutamatergic interneurons co-expressed Celsr2 in the ventral horn using double immunostaining (Supplementary Fig.…”

Genetic Mapping of Progressive Ethanol Consumption in the Diversity Outbred Mouse

“…The significant bQTL for last week mean 30% choice on Chr 3 had four notable genes, including Celsr2 and Sypl2 , which both had coding sequence variants, and Eps8l3 and Gstm5 , which had association data in GWAS Catalog with alcohol-associated traits (Table 4). Celsr2 encodes a transmembrane protein and has been implicated in axon development in the forebrain[54] and regulation of motor neuron regeneration following injury [55]. Sypl2 encodes a synaptophysin-like protein, but remains relatively uncharacterized; however, it has been implicated in obesity [56, 57] and major depressive disorder [58] in human GWAS literature.…”

WNT signaling at the intersection between neurogenesis and brain tumorigenesis

“…Both CELSR2 and CELSR3 are implicated in dendrite morphogenesis. CELSR2, a core component of PCP signaling, controls motor axon regeneration through GTP-bound Rac1, Cdc42, JNK, and c-Jun signaling (Wen et al, 2022). Downregulation of CELSR2 in brain slices reduces the length of dendrites in cortical pyramidal neurons and the complexity of dendritic trees of Purkinje cells, whereas silencing of CELSR3 leads to dendritic overgrowth (Shima et al, 2002(Shima et al, , 2004(Shima et al, , 2007.…”