PLXNA1

PLXNA1 (Plexin-A1) is a transmembrane semaphorin co-receptor that, together with neuropilins, transduces guidance cues controlling axon positioning and neuronal connectivity (PMID:31690636). In the developing nervous system, PLXNA1 acts cooperatively with PLXNA3 downstream of SEMA3A to position olfactory/vomeronasal axons required for correct GnRH neuron migration, with combined loss of both plexins phenocopying the SEMA3A-null defect (PMID:31690636), and it restricts cortico-motoneuronal projections in motor cortex layer 5 neurons to constrain vocal motor connectivity [PMID:bio_10.1101_2024.10.14.618267]. PLXNA1 also serves as a receptor for the Slit3-C fragment to drive sympathetic innervation of brown adipose tissue [PMID:bio_10.1101_2024.09.24.613949], and zebrafish ortholog knockdown disrupts CNS and eye development (PMID:34054129). In cancer, PLXNA1 functions through two signaling arms: it recruits NRP1 to form a PLXNA1-NRP1 complex that potentiates AKT phosphorylation (PMID:39226661), and RUVBL1-dependent recruitment of CRAF to PLXNA1 activates MAPK signaling (PMID:35508542), with both axes promoting enzalutamide resistance in prostate cancer; PLXNA1 silencing conversely blocks MAPK signaling and suppresses esophageal carcinoma proliferation and metastasis (PMID:31383552). Engineered dimerization of PLXNA1 with NRP2 reconstitutes tumor-suppressive SEMA3F-like signaling that inhibits AKT and proliferation (PMID:41391772).

1. 2019 High

   Established that PLXNA1 acts cooperatively with PLXNA3 as a SEMA3A co-receptor to position nasal axons guiding GnRH neuron migration, resolving which plexins transduce this neuropilin-dependent cue in vivo.

   Evidence Genetic epistasis with single and double Plxna1/Plxna3 knockouts against Sema3a-null mice, with immunofluorescence of axon and GnRH neuron positioning

   PMID:31690636

   Open questions at the time

   • Does not resolve the cytoplasmic signaling cascade downstream of PLXNA1 in this pathway
   • Functional redundancy boundaries with other plexins not fully mapped
2. 2019 Medium

   Linked PLXNA1 to oncogenic MAPK signaling by showing miR-134 directly represses PLXNA1 and that PLXNA1 is required for tumor cell proliferation and metastasis.

   Evidence Dual-luciferase reporter assay for miR-134 targeting, siRNA knockdown with MAPK readout, migration/invasion assays and xenograft in esophageal carcinoma

   PMID:31383552

   Open questions at the time

   • Direct upstream ligand/receptor partner driving MAPK in this context not defined
   • Mechanism connecting PLXNA1 to MAPK pathway not established here
3. 2021 Medium

   Demonstrated an embryonic requirement for PLXNA1 orthologs in CNS and eye development, extending its role beyond specific axon guidance circuits.

   Evidence Morpholino knockdown of plxna1a and plxna1b in zebrafish embryos with developmental phenotyping

   PMID:34054129

   Open questions at the time

   • Morpholino specificity not cross-validated by mutant alleles
   • Molecular pathway underlying the developmental defect unknown
4. 2022 Medium

   Identified a RUVBL1-CRAF-PLXNA1 axis activating MAPK as a mechanism of acquired enzalutamide resistance, explaining how PLXNA1 couples to RAF signaling.

   Evidence Co-immunoprecipitation of CRAF-PLXNA1, co-overexpression, RUVBL1 inhibitor (CB-6644) treatment, and xenograft models in prostate cancer

   PMID:35508542

   Open questions at the time

   • Whether CRAF binds PLXNA1 directly or via intermediaries not resolved
   • Single-lab Co-IP without orthogonal interaction structure
5. 2024 Medium

   Defined a parallel PLXNA1-NRP1 complex that potentiates AKT activation to drive enzalutamide resistance, distinguishing an AKT arm from the MAPK arm of PLXNA1 oncogenic signaling.

   Evidence Reciprocal Co-IP of PLXNA1-NRP1, phospho-AKT assays, NRP1 inhibitor (EG01377) and AKT inhibitor treatment, knockdown with proliferation readout in prostate cancer cells

   PMID:39226661

   Open questions at the time

   • Ligand initiating the PLXNA1-NRP1-AKT axis in this context not identified
   • Relationship between the AKT and MAPK arms not integrated
6. 2024 Medium

   Showed via conditional knockdown that PLXNA1 in layer 5 motor cortex neurons normally restricts cortico-motoneuronal projections, controlling vocal motor connectivity.

   Evidence Cre-dependent in vivo knockdown of Plxna1 in mouse motor cortex layer 5 neurons; axon tracing, functional connectivity electrophysiology, vocal behavior assays (preprint)

   PMID:bio_10.1101_2024.10.14.618267

   Open questions at the time

   • Preprint, not peer-reviewed
   • Upstream guidance cue mediating projection restriction not defined
7. 2024 Medium

   Identified PLXNA1 as a receptor for the Slit3-C fragment required for sympathetic innervation of brown adipose tissue, expanding its ligand repertoire beyond semaphorins.

   Evidence Slit3-C-to-Plxna1 receptor-ligand binding assay and in vivo Plxna1 loss-of-function with innervation and cold-stimulation phenotyping in BAT (preprint)

   PMID:bio_10.1101_2024.09.24.613949

   Open questions at the time

   • Preprint, not peer-reviewed
   • Whether a co-receptor or neuropilin is required for Slit3-C signaling unknown
   • Downstream signaling not characterized
8. 2024 Low

   Reported that PLXNA1 has high extracellular-vesicle-sorting ability and can serve as an engineerable EV scaffold.

   Evidence EV fractionation, genetic fusion constructs, and EV protein-loading assays

   PMID:39508411

   Open questions at the time

   • Single-method localization without broader mechanistic validation
   • Endogenous biological significance of PLXNA1 EV sorting unknown
9. 2025 Medium

   Demonstrated that engineered PLXNA1-NRP2 dimerization reconstitutes tumor-suppressive SEMA3F-like signaling, establishing that receptor geometry dictates whether PLXNA1 output is suppressive or oncogenic.

   Evidence Bispecific antibody dimerizing PLXNA1 and NRP2, phospho-AKT and proliferation assays, and structural studies of bsAb binding sites

   PMID:41391772

   Open questions at the time

   • No in vivo confirmation reported
   • Endogenous SEMA3F/NRP2/PLXNA1 signaling thresholds not quantified

• How PLXNA1 cytoplasmic output is switched between tumor-suppressive (AKT-inhibitory) and oncogenic (AKT/MAPK-activating) modes across ligand and co-receptor contexts remains unresolved.
• No unified model linking neuropilin/co-receptor identity to downstream signaling sign
• Direct enzymatic activity of PLXNA1 not defined in the corpus
• Structural basis of context-dependent signaling not established