PLXNA3

PLXNA3 (Plexin-A3) is a transmembrane semaphorin receptor that cooperates with neuropilins and PLXNA1 to transduce class 3 semaphorin repulsive signals during neural development and immune cell regulation. Originally cloned as a brain-enriched type I membrane protein with MET-family extracellular homology but lacking intrinsic tyrosine kinase activity, PLXNA3 associates with neuropilin co-receptors to form functional Sema3A receptor complexes that trigger axon repulsion and, in monocyte-derived macrophages, Sema3A-induced apoptosis (PMID:8570614, PMID:10520995, PMID:19480842). Combined knockout of Plxna1 and Plxna3 in mice phenocopies the nasal axon patterning and GnRH neuron migration defects of Sema3a knockouts, establishing these two plexins as functionally redundant obligate receptors for SEMA3A-guided olfactory/vomeronasal axon guidance (PMID:31690636). PLXNA3 also selectively binds the A-kinase anchoring protein MTG16b in a PKA-phosphorylation-dependent manner, providing a mechanism for integrating cAMP signaling with semaphorin receptor output (PMID:20138877).

1. 1996 High

   Cloning of PLXNA3 established it as a neural transmembrane protein with MET-like extracellular architecture but no intrinsic tyrosine kinase activity, raising the question of how it transduces signals.

   Evidence cDNA cloning from human and mouse brain, MET-PLXNA3 chimera kinase assay, in situ hybridization, cell surface biotinylation

   PMID:8570614 PMID:8733135 PMID:8806646

   Open questions at the time

   • Ligand identity was unknown at this stage
   • Signaling mechanism downstream of the cytoplasmic domain was uncharacterized
   • Functional role in vivo was not addressed
2. 1999 High

   Demonstration that plexins associate with neuropilin co-receptors and are required for Sema3A-mediated axon repulsion resolved the question of how class 3 semaphorins signal, positioning PLXNA3 as a signal-transducing subunit of the semaphorin receptor complex.

   Evidence Co-immunoprecipitation of plexin-neuropilin complexes, dominant-negative truncated plexin blocking Sema3A repulsion in neurons

   PMID:10520995

   Open questions at the time

   • Relative contributions of individual plexin-A family members to Sema3A signaling in vivo were unclear
   • Identity of the tyrosine kinase associated with plexin cytoplasmic domains was not resolved
3. 2009 Medium

   Finding that PLXNA3 is upregulated during M2 macrophage differentiation and mediates Sema3A-induced apoptosis extended its function beyond neuronal guidance to immune cell regulation.

   Evidence Flow cytometry and siRNA knockdown in M-CSF-differentiated human monocytes with apoptosis readout

   PMID:19480842

   Open questions at the time

   • Downstream apoptotic pathway components linking PLXNA3 activation to cell death were not identified
   • In vivo relevance of macrophage PLXNA3-mediated apoptosis was not tested
4. 2010 Medium

   Identification of MTG16b as a PKA-regulated AKAP that selectively binds PLXNA3 (and PLXNA1 but not PLXNB1) revealed a molecular node for cross-talk between cAMP and semaphorin signaling.

   Evidence Co-immunoprecipitation with AKAP overlay and PKA phosphorylation assays

   PMID:20138877

   Open questions at the time

   • Functional consequence of MTG16b–PLXNA3 interaction on semaphorin-dependent signaling output was not measured
   • No reciprocal validation using endogenous proteins was reported
   • Cell types in which this cross-talk operates in vivo are undefined
5. 2019 High

   Genetic epistasis in double-knockout mice demonstrated that PLXNA1 and PLXNA3 are cooperative, functionally redundant receptors required for SEMA3A-guided nasal axon patterning and GnRH neuron migration, explaining why single knockouts had shown mild phenotypes.

   Evidence Plxna1/Plxna3 double-KO mice with immunofluorescence, GnRH neuron counts, and axon tracing phenocopying Sema3a KO

   PMID:31690636

   Open questions at the time

   • Whether PLXNA3 participates in Sema3A-independent guidance pathways was not addressed
   • Structural basis for PLXNA1/PLXNA3 redundancy or possible heteromeric receptor assembly is unknown

• Key open questions include the structural mechanism of PLXNA3 activation, the identity of kinases recruited to its cytoplasmic domain, and whether its roles in macrophage apoptosis and cAMP cross-talk are relevant in vivo.
• No high-resolution structure of PLXNA3 in an active signaling complex
• Downstream signaling effectors beyond GTPase-activating activity inferred from family homology are not defined for PLXNA3 specifically
• In vivo immune phenotype in Plxna3 single or double knockout remains uncharacterized