Affinage

TENM4

Teneurin-4 · UniProt Q6N022

Length
2769 aa
Mass
308.0 kDa
Annotated
2026-06-10
18 papers in source corpus 12 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TENM4 (teneurin-4) is a transmembrane cell-adhesion protein that governs cell positioning and differentiation across neural, developmental, and stem-cell contexts [PMID:bio_10.1101_2025.09.09.671438, PMID:15489520]. In the developing cortex it orchestrates radial neuron migration by toggling between two mutually exclusive adhesive modes — homophilic Ten4-Ten4 binding and heterophilic Ten4-Latrophilin binding — that are sterically incompatible at the structural level, so that homophilic interactions reduce attachment to radial glia in the cortical plate while heterophilic interactions promote neuron-glia association in the intermediate zone [PMID:bio_10.1101_2025.09.09.671438]. At sensory nerve endings TENM4 forms filamentous extracellular tethers at the neurite-laminin interface and couples mechanical force to ion-channel activation, such that its deletion or acute proteolytic disassembly abolishes touch mechanotransduction [PMID:bio_10.1101_2024.10.10.617546]. In the visual system it shapes ipsilateral retinal projections by suppressing EphB1 expression in temporal retina (PMID:37092850), and in the oligodendrocyte lineage it controls differentiation and central myelination through the balance of full-length versus exon-10-skipped (ΔE10) isoforms (PMID:41449293). During early development TENM4 is required for Wnt-dependent mesoderm induction and gastrulation: loss-of-function embryos fail to form a primitive streak, lack TOPGAL Wnt reporter activity that is partially restored by GSK3β inhibition, and cannot undergo epithelial-to-mesenchymal transition (PMID:23521771, PMID:15489520). Patient missense mutations act through a dominant-negative mechanism, causing mutant protein mislocalization in oligodendrocyte precursor cells and axon-guidance defects in zebrafish, linking TENM4 to essential tremor (PMID:26188006).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 1999 High

    Before its developmental roles were known, TENM4 (DOC4) was identified as a chromosomal locus whose promoter drives an oncogenic fusion, establishing the gene's genomic identity and transcriptional behavior.

    Evidence Translocation mapping, RT-PCR, cDNA cloning and FISH in MDA-MB-175 breast cancer cells

    PMID:10523851 PMID:10597312

    Open questions at the time
    • Does not address the native function of TENM4 protein
    • Fusion places NRG1 under DOC4 promoter rather than reflecting TENM4 activity
  2. 2004 Medium

    Genetic loss-of-function in mouse established that the TENM4 ortholog is essential for anterior-posterior axis formation and mesoderm-derived tissues, defining its first in vivo developmental requirement.

    Evidence ENU mutagenesis allelic series with phenotypic analysis and complementation tests in mouse embryos

    PMID:15489520

    Open questions at the time
    • Molecular mechanism of patterning not resolved
    • No partner or signaling pathway identified at this stage
  3. 2013 Medium

    Mechanistic dissection of the gastrulation defect placed TENM4 upstream of Wnt signaling and epithelial-to-mesenchymal transition, explaining the mesoderm-induction failure.

    Evidence Loss-of-function mouse genetics with TOPGAL reporter, GSK3β inhibitor rescue, teratoma and cadherin immunostaining assays

    PMID:23521771

    Open questions at the time
    • How TENM4 couples to Wnt pathway activation is undefined
    • Direct molecular link to GSK3β not established
  4. 2015 Medium

    Functional testing of patient mutations established a dominant-negative mode of action and connected TENM4 to a human disease.

    Evidence Oligodendrocyte precursor mislocalization assay and zebrafish mRNA injection with axon-guidance readout, plus exome sequencing

    PMID:26188006

    Open questions at the time
    • Single lab
    • Endogenous interaction partners disrupted by mutants not identified
  5. 2023 Medium

    Knockout analysis revealed TENM4 normally suppresses EphB1 to limit ipsilateral retinal projections, defining a molecular target in axon-pathfinding control.

    Evidence Anterograde/retrograde tracing, EphB1 immunostaining and visual behavior assays in Ten-m4 knockout mice

    PMID:37092850

    Open questions at the time
    • Mechanism by which TENM4 represses EphB1 unknown
    • Direct vs. indirect regulation not distinguished
  6. 2024 Medium

    An inducible intracellular-domain gain-of-function placed the TENM4 ICD upstream of sinoatrial node gene programs, expanding its signaling role beyond adhesion.

    Evidence Tet-Off Odz4-ICD expression in embryoid bodies with electrophysiology, in situ hybridization and CellChat analysis

    PMID:39462648

    Open questions at the time
    • Physiological relevance of ICD signaling in vivo not shown
    • Mechanism linking ICD to Ptn-Ncl signaling unresolved
  7. 2025 Medium

    Structural and isoform analyses resolved how TENM4 chooses between adhesive modes and how transcript balance controls myelination, defining the protein's core mechanistic logic.

    Evidence Cryo-EM with transferable surface mutagenesis and in vivo cortical migration assays (preprint); minigene splicing, ΔE10 mouse model and OPC differentiation cultures

    PMID:41449293 PMID:bio_10.1101_2025.09.09.671438

    Open questions at the time
    • Cryo-EM data on Ten2 transferred to Ten4 by mutation conservation, not direct Ten4 structure
    • Downstream effectors of the homophilic/heterophilic switch not defined
    • How isoform ratio is regulated during OPC differentiation unknown
  8. 2024 Medium

    Conditional deletion and acute disassembly established TENM4 as a direct extracellular mechanotransduction tether, a distinct biophysical role.

    Evidence Sensory neuron-specific conditional knockout, acute proteolytic TENM4 disassembly, touch behavior and electron-microscopy localization (preprint)

    PMID:bio_10.1101_2024.10.10.617546

    Open questions at the time
    • Identity of the gated ion channel(s) not established
    • Molecular link between the laminin tether and channel activation undefined
    • Preprint, single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single adhesion protein integrates mechanosensation, migration-mode switching, isoform-balanced myelination, Wnt-dependent patterning, and EphB1 suppression into a unified molecular logic remains unresolved.
  • No unifying downstream signaling pathway identified across contexts
  • Direct intracellular effectors of the cytoplasmic domain largely uncharacterized
  • Relationship between adhesive and signaling functions unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 1 GO:0098631 cell adhesion mediator activity 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 2 GO:0005576 extracellular region 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 2
Partners
ADGRL1EPHB1

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Missense mutations in TENM4 cause mislocalization of mutant proteins in oligodendrocyte precursor cells (dominant-negative mechanism), and expression of human TENM4 mRNAs harboring patient mutations in zebrafish embryos induced defects in axon guidance, establishing a dominant-negative mode of action for TENM4 mutations linked to essential tremor. In vitro mislocalization assay in oligodendrocyte precursor cells; zebrafish mRNA injection with axon guidance phenotype readout; whole-exome sequencing and segregation analysis Human molecular genetics Medium 26188006
2004 Mouse Odz4 (TENM4 ortholog) is required for establishing the anterior-posterior axis during gastrulation; a loss-of-function allele with a nonconservative amino acid change (conserved to Drosophila) disrupts mesoderm-derived tissues including somites, heart, and skeleton, demonstrating an essential role in embryonic patterning. ENU mutagenesis allelic series; RT-PCR sequencing of mutant alleles; phenotypic analysis of mouse embryos; intragenic complementation tests Genetics Medium 15489520
2013 Mouse Tenm4 is required for mesoderm induction: loss-of-function Tenm4 mutant embryos fail to form a primitive streak and embryonic mesoderm. Wnt signaling (assessed by TOPGAL reporter) is absent in mutants, GSK3β inhibitor partially rescues the phenotype and restores TOPGAL expression. Epiblast cells remain pluripotent (Pou5f1+) but cannot differentiate in a cell-autonomous manner; misexpression of E-cadherin and N-cadherin suggests failure of epithelial-to-mesenchymal transition. Loss-of-function mouse genetics; TOPGAL Wnt reporter assay; GSK3β inhibitor rescue; teratoma assay; immunostaining for E-cadherin and N-cadherin; marker gene expression analysis BMC developmental biology Medium 23521771
1999 DOC4 (an alias of TENM4) is the 5' fusion partner in a chromosomal translocation in MDA-MB-175 breast cancer cells: the dic(8;11) translocation fuses the DOC4 gene (11q13) to the neuregulin-1/HGL gene (8p12), placing expression of the resulting gamma-heregulin fusion protein under the DOC4 promoter. Gamma-heregulin is thus a fusion oncogene product, not a native NRG1 isoform. Chromosomal translocation mapping; RT-PCR; cDNA cloning and sequencing; fluorescence in situ hybridization Oncogene High 10523851 10597312
2012 Odz4/Ten-m4 protein is expressed in quiescent satellite cells but not in activated/proliferating myoblasts, establishing a role for TENM4 in marking the quiescent state of muscle stem cells; its reappearance during regeneration follows a distinct temporal pattern compared to the calcitonin receptor. Protein-level immunodetection in satellite cells during muscle regeneration; comparison with calcitonin receptor expression timing Journal of molecular histology Low 22562803
2023 Ten-m4 knockout mice show a specific increase in ipsilateral retinal ganglion cell projections to the dLGN and superior colliculus, particularly from the temporal retina. EphB1 expression in temporal retina is enhanced in KO mice, suggesting TENM4 normally suppresses EphB1-mediated ipsilateral retention at the optic chiasm. This altered projection is associated with changes in responses to ethologically relevant visual stimuli. Anterograde and retrograde tracing in Ten-m4 knockout mice; EphB1 immunostaining; behavioral visual response assay Developmental neurobiology Medium 37092850
2025 TENM4 exon 10 skipping (ΔE10), caused by a splice-site variant, impairs oligodendrocyte differentiation and produces a smaller corpus callosum in mice. Homozygous Tenm4ΔE10/ΔE10 mice show increased seizure susceptibility. During oligodendrocyte progenitor cell differentiation, total Tenm4 transcripts increase markedly and the ratio of full-length to ΔE10 isoform is maintained; an imbalance in this ratio impairs oligodendrocyte development, establishing an isoform-balance mechanism for TENM4 in myelination. Minigene splicing assay; Tenm4ΔE10 mouse model generation; pentylenetetrazole seizure susceptibility test; corpus callosum morphometry; oligodendrocyte differentiation culture assay; RT-PCR transcript quantification Molecular neurobiology Medium 41449293
2024 Odz4 intracellular domain (ICD) overexpression in embryoid bodies promotes differentiation into pacemaker-like cells with enhanced automaticity and upregulated SAN-specific genes. CellChat analysis revealed SAN-specific enrichment of Ptn-Ncl ligand-receptor signaling, placing Odz4-ICD upstream of sinoatrial node gene programs. Tet-Off inducible Odz4-ICD expression in embryoid bodies; in situ hybridization; electrophysiology (automaticity); gene expression analysis; CellChat and GO analyses FEBS letters Medium 39462648
2021 TENM4 silencing in mammary cancer cells impairs tumorsphere-forming ability, migratory capacity, and FAK (Focal Adhesion Kinase) phosphorylation, indicating TENM4 functions upstream of FAK signaling in cancer stem cell maintenance and migration. siRNA knockdown; tumorsphere formation assay; migration assay; FAK phosphorylation western blot Cancers Low 33672732
2025 Cryo-EM data of Ten2 shows that Latrophilin binding is sterically incompatible with Ten-dimerization, making homophilic and heterophilic interactions mutually exclusive. Surface mutations engineered to disrupt Ten2-Ten2 or Ten2-Latrophilin interactions are transferable to Ten4, indicating conserved binding mechanisms. In vivo, Ten4 is expressed along radial glial cell (RGC) fibers; migrating neurons switch from low to high Ten4 expression. In the cortical plate, Ten4-Ten4 homophilic interactions reduce RGC attachment, while in the intermediate zone, Ten4-Latrophilin interactions promote neuron-RGC association, demonstrating that Ten4 orchestrates cortical neuron migration by toggling between two exclusive binding modes. Single-particle cryo-EM; engineered surface mutagenesis; in vivo gene editing; super-resolution microscopy; proteomics bioRxivpreprint Medium bio_10.1101_2025.09.09.671438
2024 Sensory neuron-specific deletion of Tenm4 in mice causes profound touch insensitivity. Acute proteolytic disassembly of TENM4 at sensory endings rapidly abolishes mechanotransduction, confirming direct involvement in force transduction. Ultrastructural analysis localizes TENM4 to filamentous structures at the neurite-laminin interface, identifying it as a structural extracellular tether that couples extracellular mechanical forces to ion channel activation in mechanoreceptors. Conditional (sensory neuron-specific) Tenm4 knockout mice; acute protease-mediated TENM4 disassembly; behavioral touch sensitivity assay; ultrastructural/electron microscopy localization bioRxivpreprint Medium bio_10.1101_2024.10.10.617546

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature genetics 1069 21926972
2015 Missense mutations in TENM4, a regulator of axon guidance and central myelination, cause essential tremor. Human molecular genetics 109 26188006
1999 gamma-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line. Oncogene 50 10523851
1999 Compartmentalized expression of zebrafish ten-m3 and ten-m4, homologues of the Drosophila ten(m)/odd Oz gene, in the central nervous system. Mechanisms of development 37 10495292
2004 Mutation of l7Rn3 shows that Odz4 is required for mouse gastrulation. Genetics 32 15489520
1999 Gamma-heregulin: a fusion gene of DOC-4 and neuregulin-1 derived from a chromosome translocation. Oncogene 29 10597312
2019 Exome Sequencing Identifies TENM4 as a Novel Candidate Gene for Schizophrenia in the SCZD2 Locus at 11q14-21. Frontiers in genetics 23 30745909
2013 Mouse Tenm4 is required for mesoderm induction. BMC developmental biology 22 23521771
2021 Genetic and functional analysis reveals TENM4 contributes to schizophrenia. iScience 21 34568788
2012 Calcitonin receptor and Odz4 are differently expressed in Pax7-positive cells during skeletal muscle regeneration. Journal of molecular histology 14 22562803
2021 Identification of TENM4 as a Novel Cancer Stem Cell-Associated Molecule and Potential Target in Triple Negative Breast Cancer. Cancers 11 33672732
2020 Parkinson's Disease in Teneurin Transmembrane Protein 4 (TENM4) Mutation Carriers. Frontiers in genetics 10 33414808
2020 Genetic testing of FUS, HTRA2, and TENM4 genes in Chinese patients with essential tremor. CNS neuroscience & therapeutics 9 32196977
2022 Role and Involvement of TENM4 and miR-708 in Breast Cancer Development and Therapy. Cells 7 35011736
2023 Han family with essential tremor caused by the P421L variant of the TENM4 gene in China. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 3 36689009
2023 Ten-m4 plays a unique role in the establishment of binocular visual circuits. Developmental neurobiology 3 37092850
2025 Transcript Imbalance from TENM4 Exon Skipping: Effects on Epilepsy and Genetic Pleiotropy. Molecular neurobiology 0 41449293
2024 Odz4 upregulates SAN-specific genes to promote differentiation into cardiac pacemaker-like cells. FEBS letters 0 39462648

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