PLXNC1

PLXNC1 (VESPR/CD232) is a transmembrane plexin-family receptor characterized by a semaphorin-like domain that transduces semaphorin signals to govern immune cell activation and neural circuit formation (PMID:9586637). It was originally isolated as the cellular receptor for the poxvirus-encoded semaphorin A39R, whose binding to PLXNC1-expressing monocytes up-regulates ICAM-1 and induces cytokine production (PMID:9586637). In the nervous system, Sema7A/PLXNC1 signaling patterns connectivity: it directs topographic segregation of nigrostriatal versus mesolimbic dopaminergic pathways through differential transcriptional control of Plxnc1 (repression by Lmx1a/Lmx1b in substantia nigra neurons, enhancement by Otx2 in ventral tegmental area neurons) (PMID:29038581), and during a neonatal critical period it drives dendrite selection and glomerular enlargement in olfactory mitral/tufted cells to enable olfactory imprinting (PMID:33780330). In disease and inflammatory contexts, Sema7A/PLXNC1 binding promotes neutrophil extracellular trap formation in acute lung injury (PMID:41713818), and PLXNC1 drives gastric cancer proliferation and migration by acting upstream of IL6ST in the IL-6/STAT3 axis (PMID:32117710) and by transferring exosomal miR-92b-5p to macrophages to promote M2 polarization, with STAT3 in turn directly activating PLXNC1 transcription to form a feedback loop (PMID:39566403). PLXNC1 also physically binds GRP78 to drive ER stress, inflammation, and matrix degradation in IL-1β-treated chondrocytes (PMID:37853395).

1. 1998 High

   Established that PLXNC1 is a bona fide cell-surface receptor by isolating it as the binding partner for the viral semaphorin A39R and linking that engagement to immune activation.

   Evidence A39R.Fc affinity purification, tandem MS peptide identification, and monocyte stimulation assays in a human B cell line

   PMID:9586637

   Open questions at the time

   • Did not identify the endogenous mammalian semaphorin ligand
   • Downstream intracellular signaling effectors of the receptor were not defined
2. 2017 High

   Showed that Sema7A/PlxnC1 signaling patterns dopaminergic circuitry and that Plxnc1 expression is set by opposing transcription factors, explaining how the receptor achieves spatial specificity in vivo.

   Evidence Transcription factor knockout/overexpression, axon tracing, and genetic epistasis with rescue in mice

   PMID:29038581

   Open questions at the time

   • Did not resolve the intracellular guidance signaling cascade downstream of PlxnC1
   • Direct transcription-factor binding at the Plxnc1 locus not shown
3. 2021 High

   Demonstrated a developmental role for PlxnC1 in olfactory imprinting, establishing that Sema7A/PlxnC1 signaling drives postsynaptic dendrite selection during a critical window.

   Evidence Knockout and rescue mice, live imaging of dendrite localization, and odor behavioral assays

   PMID:33780330

   Open questions at the time

   • Molecular link between receptor engagement and dendrite/glomerular remodeling not defined
   • Critical-period timing mechanism not mechanistically explained
4. 2020 Medium

   Placed PLXNC1 upstream of IL6ST in the IL-6/STAT3 axis, implicating the receptor as a driver of gastric cancer proliferation and migration.

   Evidence shRNA knockdown, IL6ST overexpression rescue, in vitro proliferation/migration assays, xenograft, and GSEA

   PMID:32117710

   Open questions at the time

   • No direct DNA-binding assay confirming PLXNC1 acts at the IL6ST promoter
   • Mechanism by which a plexin receptor regulates IL6ST transcription unresolved
   • Single-lab finding without independent replication
5. 2023 Medium

   Identified a physical PLXNC1–GRP78 interaction that drives ER stress and inflammatory matrix degradation, extending PLXNC1 function into chondrocyte pathology.

   Evidence Co-IP, shRNA knockdown, GRP78 overexpression rescue, western blot, TUNEL, and RT-qPCR in IL-1β-treated chondrocytes

   PMID:37853395

   Open questions at the time

   • Single Co-IP without reciprocal validation or structural mapping of the interface
   • Whether interaction is direct versus complex-mediated not established
   • Single-lab finding
6. 2024 Medium

   Defined a PLXNC1–exosomal miR-92b-5p–STAT3 circuit promoting M2 macrophage polarization and a STAT3-driven feedback loop that transcriptionally sustains PLXNC1 expression.

   Evidence Exosome isolation, small RNA-seq, flow cytometry, ChIP-qPCR, dual-luciferase reporter, co-culture, and xenograft

   PMID:39566403

   Open questions at the time

   • Mechanism linking the receptor to MEK1/MSK1/CREB1-controlled exosomal miRNA loading not fully resolved
   • Single-lab finding without independent confirmation of the feedback loop
7. 2024 Low

   Flagged PLXNC1 as a candidate ATM/ATR phosphorylation substrate linked to neurite extension, hinting at kinase regulation of its neural signaling role.

   Evidence Global phosphoproteomics after ATM depletion in human neuroblastoma cells (preprint)

   PMID:bio_10.1101_2024.06.26.600760

   Open questions at the time

   • No direct mutagenesis or functional validation of the specific phosphorylation event
   • Preprint, single dataset
   • Functional consequence of phosphorylation for receptor activity unknown
8. 2025 Low

   Proposed that anti-correlated PLXNC1/SEMA7A expression along the cortical sensorimotor-association axis exerts repulsive control over cortico-cortical connectivity.

   Evidence Multispecies transcriptomic analysis and in vivo connectivity experiments (preprint)

   PMID:bio_10.1101_2025.06.26.660775

   Open questions at the time

   • Limited mechanistic detail in preprint abstract
   • Causal connectivity experiments not fully described
   • Cellular mechanism of repulsion not defined
9. 2026 Medium

   Showed that Sema7A/PlxnC1 binding promotes neutrophil extracellular trap formation in acute lung injury and that this engagement is pharmacologically druggable.

   Evidence Molecular docking, in vitro competitive binding (baicalin), ALI rat model, RNA-seq, and single-cell sequencing

   PMID:41713818

   Open questions at the time

   • Downstream signaling from PlxnC1 to NET machinery not mapped
   • Docking-based competitive inhibition not confirmed by direct structural data
   • Single-lab finding

• The intracellular signal-transduction mechanism by which PLXNC1 converts semaphorin binding into cytoskeletal, transcriptional, and immune outputs remains undefined.
• No defined cytoplasmic effector or signaling cascade for the receptor
• No structural model of ligand-receptor engagement
• Mechanism connecting a surface receptor to reported transcriptional activities (IL6ST) unresolved