PLXND1

PLXND1 (PlexinD1) is a transmembrane class 3 semaphorin receptor that transduces repulsive guidance and mechanosensory cues to control cell migration and tissue patterning across neural, vascular, and immune systems (PMID:19421194, PMID:38328196). In the nervous system it serves as the high-affinity receptor for Sema3E on proprioceptive sensory neurons, where repellent signaling establishes the specificity of monosynaptic sensory-motor reflex circuits, and it guides facial branchiomotor neuron migration in the hindbrain, where loss-of-function disrupts motoneuron positioning (PMID:19421194, PMID:26068067). PLXND1 also acts downstream of SEMA3C to inhibit cortical dendrite outgrowth [PMID:bio_10.1101_2025.10.10.681027]. In the vasculature, PLXND1 mediates repulsive Sema3D signaling from mesenchyme to guide endothelial outgrowth and controls endothelial migration and vessel formation through a GTPase-activating protein (GAP)-related domain that is the convergent target of disease-associated variants (PMID:27799363, PMID:34791216); it additionally operates as a mechanosensor of blood flow that enlarges endothelial cells and widens vessel caliber via the flow-responsive transcription factor KLF2 (PMID:38328196). Beyond canonical semaphorin signaling, PLXND1 functions in a cell-type-specific manner to direct thymocyte migration and thymic medullary topology (PMID:24312099), promotes epithelial-mesenchymal transition and invasion through PI3K/AKT activation upon binding the furin-cleaved p61-SEMA3E in colorectal cancer (PMID:35917012), and acts as a membrane scaffold that binds ORAI1 to restrain calcium influx and downstream CAMK2-autophagy signaling in endocardial endothelial cells (PMID:36017337). De novo loss-of-function mutations in PLXND1 cause Möbius syndrome (PMID:26068067), and rare variants disrupting its GAP-related domain are associated with anomalous pulmonary venous return (PMID:34791216).

1. 2009 High

   Established that PlexinD1 is the functional receptor whose ligand-defined expression pattern sets synaptic wiring specificity, showing the receptor's repulsive signaling has discrete circuit-level consequences rather than merely diffuse guidance.

   Evidence Reciprocal conditional gain/loss of Sema3e and Plxnd1 in defined mouse neuronal populations with electrophysiology and anatomical tracing

   PMID:19421194

   Open questions at the time

   • Downstream cytoplasmic effectors of Plxnd1 in sensory neurons not defined
   • Does not address whether the same signaling logic operates outside reflex circuits
2. 2013 High

   Dissected cell-autonomous versus non-cell-autonomous roles, demonstrating PlexinD1 acts non-redundantly in thymocytes for migration and in endothelium for medullary topology but is dispensable in epithelium.

   Evidence Cell-type-specific conditional knockout mice (Lck-Cre, Keratin14-Cre, Tek-Cre) with histology and immunofluorescence

   PMID:24312099

   Open questions at the time

   • Ligand driving thymocyte migration not identified in this study
   • Molecular link between endothelial PlexinD1 loss and ectopic medulla unresolved
3. 2015 Medium

   Linked PLXND1 loss-of-function to a human Mendelian disease, establishing facial branchiomotor neuron migration as a clinically relevant readout of receptor function.

   Evidence Whole-exome sequencing of Möbius syndrome patients identifying de novo mutations plus Plxnd1 mutant mouse facial branchiomotor nucleus analysis

   PMID:26068067

   Open questions at the time

   • Single lab; specific signaling pathway downstream of the migration defect not mapped
   • Ligand responsible for branchiomotor guidance not pinned down
4. 2016 High

   Separated parallel guidance branches in vascular development, showing PlexinD1 transduces repulsive Sema3D for endothelial outgrowth while a distinct Neuropilin1 branch controls actin/morphology, clarifying receptor-specific output.

   Evidence Zebrafish genetic/pharmacological epistasis with live imaging of cardinal vein endothelial migration and actin organization

   PMID:27799363

   Open questions at the time

   • Cytoplasmic effectors coupling PlexinD1 to migration in this context not defined
   • Whether PlexinD1 and Nrp1 branches cross-regulate not addressed
5. 2022 Medium

   Identified the GAP-related domain as the functional hotspot for disease-causing variants in anomalous pulmonary venous return, tying a specific structural module to endothelial migration and vascular morphogenesis.

   Evidence Whole-exome sequencing of APVR patients with variant domain mapping plus Plxnd1 knockout mouse endothelial analysis

   PMID:34791216

   Open questions at the time

   • GAP catalytic targets (substrate GTPases) not directly assayed
   • Single lab; quantitative effect of variants on GAP activity not measured
6. 2022 Medium

   Extended PLXND1 function into cancer, showing the furin-cleaved p61-SEMA3E ligand drives PLXND1-dependent EMT and invasion through PI3K/AKT, defining a pro-tumorigenic signaling axis.

   Evidence PLXND1 knockdown in colorectal cancer cells, migration/invasion assays, PI3K/AKT readouts, furin inhibition, and xenografts

   PMID:35917012

   Open questions at the time

   • Direct biochemical demonstration of p61-SEMA3E/PLXND1 binding affinity not detailed
   • Single lab; how PLXND1 engages PI3K/AKT mechanistically unresolved
7. 2022 Medium

   Revealed a non-canonical scaffolding role in which PLXND1 binds ORAI1 to restrain calcium influx and thereby tune CAMK2-autophagy signaling, expanding receptor function beyond guidance.

   Evidence Co-immunoprecipitation of PLXND1-ORAI1 in endocardial endothelial cells from atrial fibrillation model mice with calcium, CAMK2 phosphorylation, and autophagic flux readouts

   PMID:36017337

   Open questions at the time

   • Single Co-IP without reciprocal structural validation of the interaction
   • Whether scaffolding depends on semaphorin ligand engagement unknown
8. 2024 Medium

   Defined PlexinD1 as a flow mechanosensor that positively sets vessel caliber via the transcription factor KLF2, distinguishing mechanotransduction from ligand-driven guidance.

   Evidence Zebrafish and human endothelial microvascular models with flow and genetic manipulation, KLF2 activity, and caliber quantification (preprint)

   PMID:38328196

   Open questions at the time

   • Preprint; molecular mechanism by which PlexinD1 senses force not resolved
   • Relationship between mechanosensing and semaphorin-ligand signaling unclear
9. 2025 Medium

   Placed PLXND1 downstream of astrocyte-secreted SEMA3C in dendritic inhibition, implicating the receptor in disease-relevant neuronal morphology beyond axon/circuit guidance.

   Evidence RTT astrocyte conditioned media on cortical neurons with PLXND1-blocking epistasis and in vivo rescue of dendrites, synaptic activity, and behavior (preprint)

   PMID:bio_10.1101_2025.10.10.681027

   Open questions at the time

   • Preprint; intracellular signaling from PLXND1 to dendrite cytoskeleton not mapped
   • Whether SEMA3C binds PLXND1 directly versus via co-receptor not resolved

• The cytoplasmic GAP-related domain's direct substrate GTPases and the unifying mechanism connecting PLXND1's ligand-driven guidance, mechanosensing, and ORAI1-scaffolding outputs remain undefined.
• No direct identification of GTPase substrates of the GAP domain in the corpus
• No structural model integrating mechanosensing and ligand-binding modes
• Co-receptor requirements (e.g., neuropilins) across contexts not systematically resolved