CELSR2

CELSR2 is a seven-pass transmembrane atypical cadherin that functions as a core planar cell polarity (PCP) component governing ciliogenesis, neuronal migration, and axon guidance in the developing and adult nervous system (PMID:20473291, PMID:25002511). It acts upstream of or in parallel with Vangl2 and Fzd3: loss of Celsr2 disrupts the membrane distribution of these PCP proteins and compromises planar organization of ependymal cilia, producing defective CSF dynamics and hydrocephalus (PMID:20473291), while combined Celsr2/Celsr3 loss phenocopies Fzd3 inactivation in forebrain axon guidance through a Vangl-independent route (PMID:25002511). CELSR2 localizes to intercellular boundaries and neuronal processes, consistent with a contact-mediated signaling role (PMID:11891983), and engages Vangl2 and Fz6, though it is recruited to and immobilized at junctions far less efficiently than Celsr1 (PMID:36712970). In injured neural tissue CELSR2 acts as a restraint on regenerative and reactive responses: it negatively regulates motor axon regeneration and astrocyte morphological polarization by limiting GTP-loading of Rac1 and Cdc42 and JNK/c-Jun signaling, such that Celsr2 loss enhances neurite outgrowth, glial polarization, and functional recovery after injury (PMID:34983065, PMID:37186402). In the adult cortex CELSR2 is required to maintain synaptic structure and function and supports motor learning (PMID:36089108). Beyond the nervous system, CELSR2 promotes Schwann cell and glioma cell proliferation through Wnt/β-catenin signaling (PMID:32988580, PMID:41184253) and supports hepatocyte lipid accumulation, UPR-dependent ER homeostasis, and redox balance (PMID:34478580). CELSR2 is phosphorylated on serine/threonine residues by protein kinase C and casein kinase 1 upon cellular stimulation (PMID:16484285).

1. 2002 Low

   Establishing where CELSR2 protein resides was the first step toward a function: its enrichment at cell-cell interfaces pointed to contact-mediated signaling rather than a diffusible role.

   Evidence Immunohistochemistry of Celsr2 distribution in developing mouse whisker follicles and neurons

   PMID:11891983

   Open questions at the time

   • Localization by IHC only with no functional consequence tested
   • No binding partners identified
   • Does not establish a molecular activity
2. 2006 Medium

   Two parallel advances connected CELSR2 to neuronal positioning and to post-translational control: a zebrafish ortholog kept migrating motor neurons at the pial surface, while a phosphorylation assay identified the kinases that modify the receptor.

   Evidence Zebrafish celsr2 (off-road) loss-of-function imaging of nVII migration; phosphorylation assay in transfected HeLa cells with PKC/CK1/PKA/MAPK inhibitors plus rat testis immunolocalization

   PMID:16484285 PMID:17079269

   Open questions at the time

   • The phosphorylation sites on CELSR2 are not mapped
   • Functional consequence of PKC/CK1 phosphorylation not tested
   • Migration mechanism in zebrafish not linked to specific signaling partners
3. 2010 High

   This work placed CELSR2 firmly within the PCP pathway by showing it controls ependymal ciliogenesis and is required for correct membrane distribution of Vangl2 and Fzd3, defining it as upstream of or parallel to the core PCP module.

   Evidence Celsr2 knockout mice with immunostaining for Vangl2/Fzd3 localization, histology, and CSF dynamics analysis

   PMID:20473291

   Open questions at the time

   • Direct physical interaction with Vangl2/Fzd3 not shown here
   • Mechanism by which Celsr2 positions PCP proteins unresolved
   • Redundancy with Celsr3 not dissected in this study
4. 2014 High

   Genetic epistasis resolved how CELSR2 wires the forebrain, showing it acts redundantly with Celsr3 in the Fzd3 pathway but, unlike classic PCP, independently of Vangl1/2 for axon guidance.

   Evidence Conditional knockout combinations of Celsr2, Celsr3, Fzd3, and Vangl1/2 with axon tract tracing and genetic epistasis

   PMID:25002511

   Open questions at the time

   • Molecular basis of Vangl-independence not defined
   • Downstream effectors of Celsr2/3-Fzd3 axon guidance not identified
   • Direct Celsr2-Fzd3 interaction not demonstrated
5. 2020 Medium

   Beyond development, CELSR2 was linked to a defined intracellular cascade, driving Schwann cell proliferation and migration via Wnt/β-catenin signaling.

   Evidence Celsr2 siRNA in primary Schwann cells with proliferation/migration assays, luciferase reporter, western blot, and LiCl/mutant β-catenin rescue

   PMID:32988580

   Open questions at the time

   • How CELSR2 couples to Wnt/β-catenin mechanistically is unknown
   • No direct partner linking receptor to GSK3β identified
   • Single cell type and single lab
6. 2021 Medium

   A metabolic role emerged showing CELSR2 supports hepatocyte lipid accumulation, ER homeostasis via the UPR, and redox balance, with ROS scavenging rescuing the lipid phenotype.

   Evidence CELSR2 knockdown in hepatocyte cell lines with lipid staining, UPR/antioxidant western blots, ROS assay, and NAC rescue

   PMID:34478580

   Open questions at the time

   • Signaling intermediates between CELSR2 and lipid/UPR/ROS pathways unknown
   • Whether the metabolic role uses PCP-type signaling untested
   • Single lab, cell-line based
7. 2022 High

   Loss-of-function studies established CELSR2 as a negative regulator of motor axon regeneration and a maintainer of adult cortical synapses, defining its small-GTPase-restraining mechanism and an ongoing adult role.

   Evidence Constitutive and motor-neuron conditional Celsr2 KO with explant cultures, brachial plexus injury, growth cone imaging, Rac1/Cdc42/JNK/c-Jun western blots, calcium imaging, human neuron knockdown; separate adult-induced Celsr2 KO with in vivo synaptic and calcium imaging and EM

   PMID:34983065 PMID:36089108

   Open questions at the time

   • How CELSR2 restrains Rac1/Cdc42 GTP-loading is not defined
   • Link between PCP function and GTPase regulation unclear
   • Synaptic maintenance mechanism not molecularly resolved
8. 2023 Medium

   Cell-type-specific deletions extended the GTPase-restraint mechanism to reactive astrocytes and assigned cell autonomy to CELSR2's effects on injured-neuron synapse preservation.

   Evidence Astrocyte-specific and constitutive Celsr2 KO with scratch/SCI models, calcium imaging, Cdc42/Rac1 western blots and pharmacological rescue; brachial plexus avulsion with synaptic EM, RNAseq, and MHC I staining; comparative junctional FRAP and co-IP of Celsr1/Celsr2 with Vangl2/Fz6

   PMID:36593433 PMID:36712970 PMID:37186402

   Open questions at the time

   • The cell type mediating synaptic preservation not positively identified
   • Mechanism distinguishing Celsr1 from Celsr2 junctional immobilization unknown
   • Whether MHC I upregulation is causal for synapse preservation untested
9. 2025 Medium

   CELSR2 was implicated as a pro-tumor and neuroprotective target, driving glioma proliferation through Wnt/β-catenin and serving as the direct binding target of a neuroprotective antler peptide.

   Evidence CELSR2 siRNA/shRNA glioma models with Wnt/β-catenin reporters, WNT3A and GSK-3β rescue, and orthotopic nanoparticle delivery; CETSA/MST/docking peptide binding with AAV knockdown/overexpression in SAMP8 mice

   PMID:41184253 PMID:41941989

   Open questions at the time

   • Direct receptor-ligand mechanism of peptide-CELSR2 signaling unresolved
   • How CELSR2 activates Wnt/β-catenin in glioma mechanistically unknown
   • Single-lab findings without independent replication

• The molecular bridge connecting CELSR2's extracellular cadherin-PCP engagement to its intracellular control of Rac1/Cdc42, JNK/c-Jun, and Wnt/β-catenin signaling remains undefined.
• No direct cytoplasmic effector or adaptor identified
• No structural model of CELSR2 signaling
• Mechanism unifying PCP, GTPase, and Wnt roles unknown