TENM2

TENM2 (TEN2/Lasso) is a type II transmembrane cell-adhesion protein that organizes synaptic and axonal connectivity through ligand-gated trans-cellular signaling (PMID:29677516, PMID:23884953). Its extracellular region adopts a Tc-toxin-like architecture in which a large β-barrel partially encapsulates a C-terminal domain, sealed by an immunoglobulin-like domain and apposed by a β-propeller; an alternatively spliced insert within the β-propeller acts as a molecular switch, with one variant driving latrophilin (LPHN)-dependent trans-cellular signaling and the other inducing inhibitory postsynaptic differentiation (PMID:29677516). The N-terminal lectin domain of LPHN3 docks onto the TEN2 barrel at a site distant from the spliced region, and splicing controls this interaction by sterically occluding access to the LPHN-binding surface rather than altering it directly; mutation of this surface abolishes LPHN3 binding and selectively impairs excitatory but not inhibitory synapse formation, consistent with TEN2 acting within a trimeric TEN2–LPHN3–FLRT3 complex (PMID:32358586). LPHN engagement and TEN2 homodimerization are mutually exclusive, occupying distinct conserved interfaces (PMID:41991904). At inhibitory postsynapses, TEN2 binds microtubule plus-end tracking EB proteins to recruit microtubules and support GABAA receptor exocytosis (PMID:37272607), while proteolytically shed soluble TEN2 ECR diffuses to engage LPHN1 on growth cones, triggering local exocytosis and gradient-directed axon turning (PMID:30967757). In vivo, TENM2 is required for ipsilateral retinal ganglion cell projections and binocular circuit formation, acting downstream of Zic2 through regulation of EphB1 in ventral retina (PMID:23884953). Beyond the nervous system, TENM2 suppresses a brown-adipocyte (UCP1) transcriptional program in human white adipocyte precursors (PMID:28088466).

1. 2013 High

   Established that TENM2 has a non-redundant in vivo role in wiring binocular visual circuits, placing it within a defined molecular pathway for ipsilateral retinal projections.

   Evidence Ten-m2 KO mouse with axonal tracing, immunohistochemistry, visually evoked potentials, and behavior

   PMID:23884953

   Open questions at the time

   • Whether TEN-M2 regulates EphB1 directly or indirectly is not resolved
   • Molecular mechanism linking TEN-M2 to Zic2/EphB1 not biochemically defined
2. 2017 Medium

   Extended TENM2 function beyond neurons by showing it represses a thermogenic transcriptional program in adipocyte precursors.

   Evidence siRNA knockdown in human SGBS preadipocytes with qRT-PCR, western blot, and Seahorse respirometry

   PMID:28088466

   Open questions at the time

   • Mechanism by which TENM2 suppresses UCP1 is unknown
   • No link established between adipocyte role and the synaptic/adhesion functions
3. 2018 High

   Solved the architecture of the TEN2 extracellular region and identified an alternatively spliced β-propeller insert as the switch toggling between LPHN-dependent excitatory signaling and inhibitory postsynaptic differentiation.

   Evidence 3.1 Å single-particle cryo-EM with splice-variant functional assays

   PMID:29677516

   Open questions at the time

   • Structural basis for how the splice switch is decoded into opposing synaptic outcomes not fully defined
   • No structure of TEN2 bound to a partner in this study
4. 2019 Medium

   Defined a paracrine mode in which proteolytically shed soluble TEN2 acts as a diffusible LPHN1 ligand directing axon guidance, distinguishing it from membrane-tethered adhesion signaling.

   Evidence Affinity isolation of TEN2/Lasso as LPHN1 ligand, growth-cone turning imaging, and LPHN1 KO epistasis

   PMID:30967757

   Open questions at the time

   • Identity of the protease(s) that shed TEN2 not established
   • Intracellular signaling cascade downstream of LPHN1 redistribution not detailed
5. 2019 Medium

   Identified TEN2 and LPHN1 co-upregulation in reactive astrocytes after brain injury, with TCAP-1 eliciting calcium signaling, implicating the pathway in injury responses.

   Evidence Immunohistochemistry, RT-PCR, and intracellular calcium imaging after mechanical injury / TCAP-1 treatment

   PMID:31316338

   Open questions at the time

   • Causal role of TEN2 in the astrocyte injury response not tested by loss-of-function
   • Relationship between TCAP-1 calcium signaling and full-length TEN2 function unclear
6. 2020 High

   Resolved how alternative splicing controls LPHN3 binding — by sterically occluding a distant binding surface — and showed this interaction selectively drives excitatory synapse formation within a TEN2–LPHN3–FLRT3 trimer.

   Evidence 2.9 Å cryo-EM of the TEN2–LPHN3 complex with mutagenesis and synapse formation assays

   PMID:32358586

   Open questions at the time

   • Structural basis of the inhibitory-synapse branch not resolved
   • Stoichiometry and assembly dynamics of the trimeric complex in cells not defined
7. 2023 Medium

   Provided a cytoplasmic effector mechanism for inhibitory synapse function by linking TEN2 to microtubule plus ends via EB proteins to support GABAA receptor delivery.

   Evidence Live imaging, reciprocal Co-IP with EB proteins, fractionation, and GABAA receptor exocytosis assay

   PMID:37272607

   Open questions at the time

   • Whether the EB interaction is direct or bridged not established
   • Connection between the splice switch and EB recruitment not defined
8. 2026 High

   Showed that LPHN binding and TEN2 homodimerization are mutually exclusive structural states, defining how distinct interfaces partition TEN2 into competing signaling modes.

   Evidence Cryo-EM with interface-specific surface mutagenesis, proteomics, super-resolution microscopy, and in vivo gene editing

   PMID:41991904

   Open questions at the time

   • Cellular triggers that bias TEN2 toward homodimer versus LPHN complex unknown
   • Functional consequence of homodimerization in vivo not fully defined
9. 2026 Medium

   Confirmed coordinated upregulation of Ten-2 and ADGRL1/latrophilin-1 in reactive astrocytes during seizure-induced neurodegeneration, generalizing the injury-response role across pathologies.

   Evidence Immunohistochemistry, qRT-PCR, Fluoro-Jade C staining in a LiCl-pilocarpine status epilepticus rat model

   PMID:41930255

   Open questions at the time

   • Functional role of astrocytic TEN2–ADGRL1 in neurodegeneration not tested by perturbation
   • Whether upregulation is protective or pathogenic unknown

• How a single extracellular splice/dimerization switch is decoded into the opposing outcomes of excitatory versus inhibitory synapse formation, and how this integrates with cytoplasmic EB-microtubule signaling, remains unresolved.
• No structure of the inhibitory-synapse signaling state
• Mechanism coupling extracellular conformational state to intracellular GABAA receptor trafficking unknown