PLXNA4

PLXNA4 is a transmembrane semaphorin receptor that transduces repulsive and guidance cues in the developing nervous and cardiovascular systems. As a receptor for SEMA3A, PLXNA4 signals through its intrinsic GAP catalytic domain to control hippocampal mossy fiber tract partitioning, laminar targeting, and axon bundling, and through a SEMA3A–PLXNA4–FYN signaling axis to promote neural differentiation [PMID:35163445, PMID:bio_10.1101_2024.12.15.628586]. Its full-length isoform (TS1) specifically increases tau phosphorylation upon SEMA3A stimulation, whereas shorter isoforms oppose this effect (PMID:25043464). PLXNA4 expression in cortical neurons is transcriptionally regulated by FoxO6 and MED13, and ectopic PLXNA4 expression rescues defective radial neuronal migration and callosal projection caused by loss of either transcription factor (PMID:27791111, PMID:41663567).

1. 2014 Medium

   Establishing that PLXNA4 isoforms differentially regulate tau phosphorylation downstream of SEMA3A resolved how alternative splicing at this receptor could produce opposing signaling outputs relevant to tauopathy.

   Evidence Isoform-specific transfection of SH-SY5Y cells and primary rat neurons with SEMA3A stimulation and tau phosphorylation readout

   PMID:25043464

   Open questions at the time

   • Single-lab observation not independently replicated
   • Downstream kinase cascade linking PLXNA4 TS1 to tau phosphorylation not identified
   • In vivo relevance of isoform-specific tau phosphorylation not tested
2. 2016 High

   Demonstrating that FoxO6 directly binds the Plxna4 promoter and that ectopic Plxna4 rescues FoxO6-deficient cortical migration defects established PLXNA4 as a critical transcriptional effector of radial neuronal migration.

   Evidence ChIP for FoxO6 at Plxna4 promoter, transcriptomics, and in utero electroporation rescue in mouse cortex

   PMID:27791111

   Open questions at the time

   • Whether FoxO6 regulation of PLXNA4 operates in non-cortical neuron populations is unknown
   • The semaphorin ligand mediating migration in this context is not defined
3. 2022 Medium

   Identifying a SEMA3A–PLXNA4–FYN signaling axis in neural differentiation of mesenchymal stem cells extended PLXNA4 function beyond axon guidance to progenitor cell fate decisions.

   Evidence PLXNA4 knockdown/overexpression with FYN activation assay and RNA-seq in human umbilical cord mesenchymal stem cells

   PMID:35163445

   Open questions at the time

   • Single-lab finding; FYN activation as mediator not confirmed by independent study
   • Whether this axis operates during in vivo neurogenesis is untested
4. 2024 Medium

   Showing that PlxnA4 knockout and GAP-domain mutant mice phenocopy hippocampal mossy fiber defects established that the intrinsic GAP catalytic activity is required for tract partitioning and laminar targeting.

   Evidence Plxna4 knockout and GAP catalytic domain mutant mice with immunohistochemistry and axon tracing (preprint)

   PMID:bio_10.1101_2024.12.15.628586

   Open questions at the time

   • Preprint; not yet peer-reviewed
   • The Rap/Ras GTPase substrate of the GAP domain in mossy fibers is not identified
   • Whether semaphorin ligand binding is also required for these phenotypes is not fully dissected
5. 2025 Medium

   Demonstrating that PlxnA4 mRNA is locally translated in dopaminergic axons and modulates nigrostriatal arborization revealed a mechanism for circuit-specific spatial control of PLXNA4 signaling.

   Evidence RiboTag axon-specific ribosome profiling with in vitro and in vivo Sema3a functional assays (preprint)

   PMID:bio_10.1101_2025.11.25.690389

   Open questions at the time

   • Preprint; not yet peer-reviewed
   • Cis-regulatory elements controlling local translation are not mapped
   • Contribution of local vs. somatic PLXNA4 protein pools not quantified
6. 2025 Medium

   Loss of cardiac sympathetic innervation and arrhythmogenesis in PlexinA3/A4 double knockouts established PLXNA4 as a guidance receptor for cardiac sympathetic nerve development, linking semaphorin signaling to cardiac electrophysiology.

   Evidence PlexinA3/A4 double KO mice with tissue clearing, optical mapping, ECG, and β-adrenergic receptor quantification (preprint)

   PMID:bio_10.1101_2025.05.20.655085

   Open questions at the time

   • Preprint; not yet peer-reviewed
   • Individual contribution of PLXNA4 vs. PLXNA3 not resolved
   • The semaphorin ligand directing cardiac sympathetic guidance is not identified
7. 2026 Medium

   Identification of PLXNA4 as a downstream effector of MED13 that specifically rescues radial migration and callosal projection (but not dendritic complexity) revealed pathway-selective functions of PLXNA4 in cortical development.

   Evidence Med13 knockdown proteomics in SH-SY5Y cells and PlxnA4 overexpression rescue via in utero electroporation

   PMID:41663567

   Open questions at the time

   • Whether MED13 regulation of PLXNA4 is transcriptional or post-transcriptional is not resolved
   • The mechanism by which PLXNA4 selectively rescues migration but not dendritic complexity is unknown

• The identity of the Rap/Ras GTPase substrates of the PLXNA4 GAP domain in vivo, the structural basis for isoform-specific signaling divergence, and the mechanisms underlying potential non-neuronal metabolic roles remain unresolved.
• No in vivo GAP substrate identification
• No structural model of full-length PLXNA4 or isoform-specific differences
• Metabolic phenotype in zebrafish lacks defined molecular mechanism