PLXNA4

PLXNA4 is a semaphorin receptor that transduces SEMA3A and Sema6A signals to direct axon guidance, neuronal migration, and circuit assembly during nervous system development [PMID:27791111, PMID:bio_10.1101_2025.11.25.690389]. It operates as a transcriptional effector node: FoxO6 binds DAF-16 elements in the Plxna4 promoter and the transcriptional regulator Med13 acts upstream, with ectopic PlxnA4 expression rescuing the cortical neuron radial migration and callosal projection defects produced by loss of either factor, placing Plxna4 downstream in these migration pathways (PMID:27791111, PMID:41663567). PLXNA4 signaling engages FYN kinase as a downstream effector during SEMA3A-driven neuronal differentiation (PMID:35163445), and its intrinsic GAP catalytic activity is required for hippocampal mossy fiber partitioning, axon bundling, and laminar targeting [PMID:bio_10.1101_2024.12.15.628586]. In dopaminergic neurons, Plxna4 mRNA is locally translated within axons to modulate Sema3a-dependent arborization and nigrostriatal targeting [PMID:bio_10.1101_2025.11.25.690389]. PLXNA4 acts in an isoform-specific manner: the full-length TS1 isoform increases tau phosphorylation upon SEMA3A stimulation while shorter isoforms have the opposite effect, without affecting APP processing or Aβ production (PMID:25043464). Beyond neurodevelopment, PlexinA4 (together with PlexinA3) guides cardiac sympathetic innervation, with its loss producing adrenergic hypersensitivity and ventricular arrhythmias [PMID:bio_10.1101_2025.05.20.655085], and loss of Plxna4 in zebrafish increases adiposity and food intake [PMID:bio_10.1101_2025.03.15.643290].

1. 2014 Medium

   Established that PLXNA4 isoforms differentially couple SEMA3A signaling to tau phosphorylation, linking a semaphorin receptor to a neurodegeneration-relevant readout and ruling out an amyloid route.

   Evidence Isoform transfection into SH-SY5Y cells and primary rat neurons with SEMA3A stimulation and tau phosphorylation assay; APP-stable HEK293 negative control

   PMID:25043464

   Open questions at the time

   • Mechanism connecting receptor signaling to tau kinases not defined
   • Overexpression-based, no endogenous isoform validation
   • In vivo relevance not tested
2. 2016 High

   Placed Plxna4 downstream of FoxO6 in cortical radial migration, defining a transcription-factor-to-receptor pathway controlling neuronal positioning.

   Evidence FoxO6 promoter-binding assay, siRNA knockdown, in utero electroporation with ectopic Plxna4 rescue, and transcriptome analysis

   PMID:27791111

   Open questions at the time

   • Ligand and downstream effectors for migration not identified
   • Whether FoxO6 binding is direct in vivo not fully resolved
3. 2022 Medium

   Identified FYN kinase as a downstream effector of SEMA3A→PLXNA4 signaling during neuronal differentiation, extending the receptor's signaling output.

   Evidence siRNA knockdown and recombinant protein addition in hUC-MSCs undergoing neural differentiation, RNA sequencing, and FYN activation assay

   PMID:35163445

   Open questions at the time

   • Mechanism of FYN activation by PLXNA4 not defined
   • Non-neuronal differentiation model
   • Single lab
4. 2024 Medium

   Demonstrated that the PlxnA4 GAP catalytic domain is required for hippocampal mossy fiber tract partitioning and laminar targeting, distinguishing enzymatic from structural receptor roles.

   Evidence Plxna4 knockout and GAP catalytic mutant knock-in mice with axon tract analysis (preprint)

   PMID:bio_10.1101_2024.12.15.628586

   Open questions at the time

   • GAP substrate (target GTPase) not identified in this system
   • Preprint not peer-reviewed
5. 2025 Medium

   Showed Plxna4 is locally translated in dopaminergic axons to control Sema3a-dependent arborization and nigrostriatal targeting, adding spatial regulation of receptor expression.

   Evidence RiboTag axon-specific ribosome profiling in DAT-Cre mice with in vitro and in vivo arborization/targeting assays (preprint)

   PMID:bio_10.1101_2025.11.25.690389

   Open questions at the time

   • Mechanism targeting mRNA to axons unknown
   • Downstream signaling in mDA axons not mapped
   • Preprint
6. 2025 Medium

   Extended PlexinA4 function beyond CNS, showing it (with PlexinA3) guides cardiac sympathetic innervation, with loss causing arrhythmia via adrenergic hypersensitivity.

   Evidence PlexinA3/A4 double knockout mouse with tissue clearing, echocardiography, ECG, optical mapping, catecholamine and β-adrenergic receptor density measurements (preprint)

   PMID:bio_10.1101_2025.05.20.655085

   Open questions at the time

   • PlexinA4-specific contribution confounded by double knockout
   • Ligand driving cardiac innervation not defined
   • Preprint
7. 2025 Medium

   Revealed a non-neuronal-circuit phenotype, with Plxna4 loss increasing adiposity and food intake in zebrafish, implicating it in feeding regulation.

   Evidence Zebrafish plxna4 loss-of-function mutants with body fat quantification, feeding and locomotor assays (preprint)

   PMID:bio_10.1101_2025.03.15.643290

   Open questions at the time

   • Neural circuit or cell type mediating feeding effect unknown
   • Whether mammalian PLXNA4 has the same role untested
   • Preprint

• The molecular link between PLXNA4 GAP activity, its GTPase substrate, and the diverse downstream effectors (FYN, tau kinases) remains unresolved across its developmental and metabolic roles.
• No identified GTPase substrate for the GAP domain in any system
• Unified signaling model connecting ligand binding to cytoskeletal/transcriptional outputs absent
• Direct structural data on ligand-receptor engagement not in corpus