Affinage

TBR1

T-box brain protein 1 · UniProt Q16650

Length
682 aa
Mass
74.1 kDa
Annotated
2026-06-10
58 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TBR1 is a neuron-specific T-box transcription factor that functions as a terminal determinant of postmitotic cortical projection-neuron identity, acting at the end of the Pax6→Tbr2→Tbr1 differentiation cascade in the developing neocortex (PMID:15634788, PMID:30186101). It implements both regional (frontal vs. caudal) and laminar (layer 6 vs. layer 5) neuronal identity through bidirectional transcriptional control: it directly represses Fezf2 in layer 6 corticothalamic neurons to restrict the corticospinal tract to layer 5, while activating frontal/layer 6 identity programs including Auts2 and Sox5 (PMID:20615956, PMID:21285371, PMID:21228164). TBR1 and Fezf2 form a mutual repression circuit, and TBR1 expression is itself dosage-controlled by upstream repressors such as BCL11A/CTIP1 to partition layer 6 from layer 5 fates (PMID:21228164, PMID:25972180). Beyond fate specification, TBR1 governs neuronal maturation—directing dendritic patterning, synaptogenesis, and intrinsic physiology of layer 6 neurons via a transcriptional circuit that includes Wnt7b and Kif1a, with WNT-signaling agonists (LiCl, GSK3β inhibitors) rescuing the spine, synaptic, and axonal defects of Tbr1 mutants (PMID:30318412, PMID:32294447, PMID:35123407). In mature neurons TBR1 couples activity to gene expression, driving CaMKII-dependent induction of the NMDAR subunit gene Grin2b (PMID:25309323). The T-box domain binds palindromic T-box elements as a dynamically exchanging monomer/dimer, and TBR1 acts together with co-regulators CASK, FOXP2, BCL11A and a broad interactome of ~250 partners enriched for neurodevelopmental-disorder proteins (PMID:25232744, PMID:36579832, PMID:41237949). ChIP-seq positions TBR1 as a direct regulator of a network of autism risk genes, and de novo truncating and missense mutations disrupt DNA binding, protein interactions, and subcellular localization, linking TBR1 to autism spectrum disorder (PMID:25232744, PMID:27325115, PMID:30250039). TBR1 additionally directs laminar dendrite targeting of specific retinal ganglion cell subtypes through downstream effectors Sorcs3 and Cdh8 (PMID:29632360, PMID:30995485).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2005 High

    Established TBR1's position in the cortical differentiation hierarchy, answering where in neurogenesis it acts.

    Evidence In situ hybridization and immunostaining of developing mouse neocortex defining the Pax6→Tbr2→Tbr1 sequence

    PMID:15634788

    Open questions at the time
    • Expression sequence alone does not establish direct regulatory targets
    • Does not define which downstream genes TBR1 controls
  2. 2010 High

    Showed TBR1 controls both regional and laminar identity and acts as both activator and repressor, defining its dual transcriptional logic.

    Evidence Tbr1 knockout microarrays, ChIP at the Auts2 promoter, and Sox5 genetic epistasis in mouse cortex

    PMID:20615956

    Open questions at the time
    • Mechanism of repression vs. activation switching unresolved
    • Direct vs. indirect status of many regulated genes not distinguished
  3. 2010 High

    Identified upstream epigenetic control of Tbr1, showing how AF9/DOT1L-mediated H3K79 methylation gates its expression and how AF9 affects TBR1 localization.

    Evidence Af9 knockout, ChIP for AF9 and H3K79me2 at the Tbr1 TSS, AF9-DOT1L Co-IP, and immunofluorescence

    PMID:20348416

    Open questions at the time
    • Functional consequence of mitochondrial TBR1 association unexplained
    • Does not address transcriptional targets of TBR1 itself
  4. 2011 High

    Defined the direct molecular mechanism by which TBR1 segregates corticothalamic from corticospinal fate via Fezf2 repression and a mutual repression circuit.

    Evidence Tbr1 KO/misexpression with axon tracing, ChIP at the Fezf2 locus, and Tbr1/Fezf2 compound mutant epistasis

    PMID:21228164 PMID:21285371

    Open questions at the time
    • Co-factors required for Fezf2 repression not identified
    • Cis-regulatory architecture of the repressed Fezf2 region not fully mapped
  5. 2014 High

    Connected TBR1 haploinsufficiency to circuit-level and behavioral deficits and demonstrated pharmacological reversibility, establishing disease relevance and a candidate intervention point.

    Evidence Tbr1+/− mice with amygdalar connectivity, c-FOS/GRIN2B readouts, and d-cycloserine rescue

    PMID:24441682

    Open questions at the time
    • Whether GRIN2B is a direct vs. indirect target not resolved here
    • Generalizability of NMDA-agonist rescue beyond amygdala unknown
  6. 2014 High

    Demonstrated that disease-associated TBR1 mutations are functionally pathogenic, linking ASD genetics to specific molecular defects in localization, dimerization, and FOXP2 interaction.

    Evidence Functional assays in transfected cells (localization, luciferase, Co-IP for homodimerization and FOXP2) on patient variants

    PMID:25232744

    Open questions at the time
    • In vitro assays may not capture in vivo neuronal consequences
    • Which variant-disrupted interactions drive phenotype not pinpointed
  7. 2014 Medium

    Placed TBR1 in an activity-dependent signaling loop in mature neurons, showing it transduces CaMKII signaling into Grin2b induction.

    Evidence Pharmacological stimulation of cultured neurons, Tbr1-deficient neurons, Grin2b promoter luciferase, and KN-93 CaMKII inhibition

    PMID:25309323

    Open questions at the time
    • Single-lab study
    • How CaMKII signaling reaches the Tbr1 gene/protein mechanistically not defined
  8. 2015 Medium

    Identified BCL11A/CTIP1 as a dosage-dependent upstream repressor of Tbr1, refining how layer 5 vs. layer 6 fate boundaries are set.

    Evidence CTIP1 conditional KO/knockdown with direct repression assay and layer marker analysis

    PMID:25972180

    Open questions at the time
    • Single lab
    • Direct binding to the Tbr1 locus by CTIP1 not fully resolved
  9. 2017 Medium

    Revealed a developmental shift in TBR1 localization (nuclear embryonic to cytoplasmic/synaptic adult) and identified CASK as an activity-enhancing co-regulator.

    Evidence DAB staining, confocal imaging, and synaptosomal fractionation of adult cortex/hippocampus

    PMID:17329080

    Open questions at the time
    • Single lab
    • Functional role of synaptic TBR1 pool not mechanistically established
  10. 2017 Medium

    Mapped the CASK-TBR1 interaction to a specific residue and tied it to cognitive flexibility, distinguishing memory extinction from acquisition.

    Evidence CASK-TBR1 Co-IP, CASK T740A knock-in mice, and fear/taste-aversion behavioral assays

    PMID:28234597

    Open questions at the time
    • Single lab
    • Downstream transcriptional changes driving the behavioral phenotype not identified
  11. 2017 Medium

    Identified post-transcriptional control of the Tbr1 transcript by the Microprocessor, a miRNA-independent layer regulating TBR1+ neuron production.

    Evidence Conditional Dgcr8 vs. Dicer KO comparison and transcript analysis in mouse cortex

    PMID:28232627

    Open questions at the time
    • Single lab
    • Mechanism of hairpin cleavage and its quantitative effect on TBR1 protein unresolved
  12. 2016 High

    Provided genome-wide evidence that TBR1 directly regulates a network of ASD risk genes, generalizing it from single-gene control to an ASD transcriptional hub.

    Evidence TBR1 ChIP-seq and Tbr1 KO RNA-seq in embryonic mouse cortex with enrichment analysis

    PMID:27325115

    Open questions at the time
    • Binding adjacency does not prove direct functional regulation of every gene
    • Cell-type resolution within cortex limited
  13. 2018 High

    Linked TBR1 to neuronal maturation beyond fate specification, identifying Wnt7b as a key effector whose restoration rescues synaptic deficits.

    Evidence Layer 6 conditional Tbr1 deletion with ChIP-seq, RNA-seq, patch-clamp, and viral Wnt7b rescue

    PMID:30318412

    Open questions at the time
    • Other maturation targets beyond Wnt7b not fully accounted for
    • Mechanism connecting Wnt7b to specific synaptic readouts not detailed
  14. 2018 High

    Extended TBR1 function to retinal circuit assembly, showing it specifies laminar dendrite targeting of RGC subtypes through transmembrane effectors.

    Evidence Tbr1 retinal conditional KO and misexpression with RGC morphology and Sorcs3/Cdh8 effector identification

    PMID:29632360

    Open questions at the time
    • How Sorcs3/Cdh8 mechanistically direct dendrite lamination not resolved
    • Relationship between cortical and retinal TBR1 programs unclear
  15. 2018 High

    Integrated TBR1 into a feedforward/feedback cascade with Pax6 and Tbr2 and linked it to chromatin regulation via non-canonical PRC1.

    Evidence ChIP-seq for Pax6/Tbr2/Tbr1 and expression analysis across TF mutant cortices

    PMID:30186101

    Open questions at the time
    • Direct demonstration of ncPRC1 assembly downstream of Tbr1 not shown
    • Epigenetic consequences at specific loci not mapped
  16. 2018 Medium

    Expanded the TBR1 interactome to BCL11A and showed that in silico variant predictions do not reliably equal functional disruption, refining variant interpretation.

    Evidence Subcellular localization, transcriptional assays, and BRET interaction tests of T-box missense variants

    PMID:30250039

    Open questions at the time
    • Single lab
    • In vivo consequences of functionally disruptive variants not tested
  17. 2019 Medium

    Showed a gain-of-function DNA-binding-dead allele (K228E) produces distinct phenotypes from loss of function, including altered interneuron distribution and inhibitory transmission.

    Evidence K228E knock-in mice with RNA-seq, immunostaining, and patch-clamp electrophysiology

    PMID:31680851

    Open questions at the time
    • Single lab
    • Mechanism of TBR1-K228E protein upregulation unexplained
  18. 2019 Medium

    Demonstrated TBR1 is required for formation and maintenance of specific orientation-selective and OFF-sustained RGC types, deepening its retinal role.

    Evidence Tbr1 retina KO and ectopic expression in M4 ipRGCs with morphological/functional RGC analysis

    PMID:30995485

    Open questions at the time
    • Single lab
    • Effector genes for these specific RGC types not all identified
  19. 2020 High

    Established WNT signaling as a druggable downstream node, showing LiCl and GSK3β inhibitors rescue spine, synaptic, and axonal defects of Tbr1 mutants.

    Evidence Tbr1 conditional KO with spine/synapse morphometry, Kif1a/Wnt7b expression analysis, and pharmacological rescue

    PMID:32294447

    Open questions at the time
    • Whether rescue normalizes circuit function/behavior not addressed here
    • Direct TBR1 binding at all rescued targets not shown
  20. 2022 Medium

    Showed rescue is achievable in adult brain, demonstrating ongoing requirement for TBR1 and reversibility of synaptic deficits after development.

    Evidence Adult layer 5/6 conditional Tbr1 KO with mEPSC/mIPSC recording, spine analysis, and LiCl rescue

    PMID:35123407

    Open questions at the time
    • Single lab
    • Durability of pharmacological rescue not assessed
  21. 2022 Medium

    Demonstrated that distinct patient mutations cause allele-specific phenotypes (loss vs. gain), explaining mutation-specific clinical heterogeneity while converging on shared defects.

    Evidence Allelic series of patient-specific Tbr1 knock-in mice with layer marker immunostaining and brain structure quantification

    PMID:35944998

    Open questions at the time
    • Single lab
    • Molecular basis of K228E-specific layering defects not fully resolved
  22. 2023 High

    Defined the global TBR1 protein interaction landscape and mapped two distinct protein-binding domains, framing TBR1 as a hub for NDD-associated proteins.

    Evidence AP-MS interactome (~250 partners) with BRET validation and NDD variant interaction testing

    PMID:36579832

    Open questions at the time
    • Most of the ~250 partners not individually validated
    • Functional consequences of most interactions unknown
  23. 2023 Medium

    Identified Pou4f1 as a direct upstream activator of Tbr1 in retina, establishing a Pou4f1→Tbr1→Jam2 hierarchy for J-RGC formation.

    Evidence CUT&Tag chromatin binding, Pou4f1 conditional KO, and enhancer reporter assays in J-RGCs

    PMID:38469155

    Open questions at the time
    • Single lab
    • Whether the same upstream regulation applies in cortex not tested
  24. 2025 High

    Provided biophysical mechanism for TBR1-DNA recognition, showing single vs. palindromic TBE occupancy and dynamic monomer sliding that enables dual occupancy.

    Evidence Single-molecule FRET, isothermal titration calorimetry, and molecular dynamics on the T-box domain and TBE

    PMID:41237949

    Open questions at the time
    • Behavior on native chromatin with co-factors not assessed
    • Link between binding kinetics and transcriptional output not established
  25. 2025 Medium

    Revealed a non-neuronal role for TBR1 in corneal stroma, placing it upstream of Smad4-dependent ECM homeostasis via Cathepsin B regulation.

    Evidence Keratocyte-specific Tbr1, Smad4, and double KO mice with corneal OCT, collagen staining, and Cathepsin B inhibitor rescue

    PMID:39894408

    Open questions at the time
    • Single lab and novel tissue context
    • Whether TBR1 directly binds Cathepsin B/Smad4-related loci not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TBR1's DNA-binding kinetics, its ~250-member interactome, and its switch between activator and repressor states combine to select cell-type-specific target programs across cortex, retina, and cornea remains unresolved.
  • No unified model linking co-factor identity to activator vs. repressor output
  • Functional roles of most interactome partners uncharacterized
  • Mechanism switching nuclear developmental vs. cytoplasmic/synaptic adult pools unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 5 GO:0003677 DNA binding 4
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 2
Pathway
R-HSA-1266738 Developmental Biology 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-112316 Neuronal System 4
Partners
BCL11ACASKFOXP2

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 TBR1 is expressed sequentially after TBR2 in postmitotic projection neurons during neocortical development, delineating the transcription factor cascade Pax6 → Tbr2 → Tbr1 in the differentiation of radial glia → intermediate progenitor cell → postmitotic projection neuron. In situ hybridization and immunostaining in developing mouse neocortex The Journal of neuroscience High 15634788
2010 TBR1 exerts positive and negative transcriptional control over both regional (frontal vs. caudal) and laminar (layer 6 vs. layer 5) identity of postmitotic cortical neurons; Tbr1 null mice show downregulation of frontal/layer 6 markers (Bcl6, Cdh9) and upregulation of caudal/layer 5 markers (Bhlhb5, Fezf2). TBR1 directly binds and activates the Auts2 promoter to implement frontal identity, and activates Sox5 to regulate laminar identity and corticofugal axon projections. Tbr1 knockout mouse analysis, gene expression microarrays, chromatin immunoprecipitation (promoter binding of Auts2), genetic epistasis with Sox5 mutants Proceedings of the National Academy of Sciences of the United States of America High 20615956
2011 TBR1 directly represses Fezf2 transcription by binding the Fezf2 locus in layer 6 corticothalamic neurons, restricting the origin of the corticospinal tract to layer 5. In Tbr1 null mutants, corticospinal axons ectopically originate from layer 6 neurons in a Fezf2-dependent manner; misexpression of Tbr1 in layer 5 CS neurons suppresses Fezf2 and abolishes the CS tract. Tbr1 knockout and misexpression in vivo, chromatin immunoprecipitation showing TBR1 binding to Fezf2 locus, genetic epistasis (Tbr1 null vs. Fezf2-dependent rescue) Proceedings of the National Academy of Sciences of the United States of America High 21285371
2011 TBR1 promotes corticothalamic (layer 6) neuronal identity and represses subcerebral (layer 5) fates by reducing expression of Fezf2 and CTIP2. ChIP shows TBR1 binds a conserved region in the Fezf2 gene. Compound Tbr1/Fezf2 mutant analysis shows Fezf2 blocks corticothalamic fate in layer 5 by reducing Tbr1 expression, establishing a mutual repression circuit. Tbr1 knockout mouse phenotyping, ectopic Tbr1 expression in layer 5 neurons, ChIP with TBR1 antibodies at Fezf2 locus, Fezf2/Tbr1 compound mutant genetic epistasis The Journal of neuroscience High 21228164
2014 TBR1 haploinsufficiency alters expression of Ntng1, Cntn2, and Cdh8, reduces inter- and intra-amygdalar axonal connections, decreases c-FOS-positive neurons and prevents GRIN2B induction in the amygdala upon behavioral stimulation. Upregulation of amygdalar neuronal activity by local infusion of d-cycloserine (a partial NMDA receptor agonist) ameliorates behavioral deficits of Tbr1+/− mice. Tbr1 heterozygous knockout mice, behavioral assays, immunostaining, c-FOS quantification, pharmacological rescue with d-cycloserine Nature neuroscience High 24441682
2014 De novo truncating and missense TBR1 mutations found in sporadic autism disrupt subcellular localization, interactions with co-regulators, and transcriptional repression. TBR1 homodimerizes and interacts with FOXP2; pathogenic mutations affecting either TBR1 or FOXP2 disrupt this interaction. Missense mutations inherited from unaffected parents did not disturb these functions. Functional assays in transfected cells (subcellular localization, luciferase transcriptional assays, co-immunoprecipitation for homodimerization and FOXP2 interaction), analysis of ASD patient mutations Nature communications High 25232744
2014 TBR1 is required for the induction of Grin2b (NMDAR subunit NR2B) upon neuronal activation in mature neurons. Neuronal excitation (via bicuculline or glutamate) upregulates Tbr1 mRNA and protein in a CaMKII-dependent (but calcineurin-independent) manner, and elevated Tbr1 drives Grin2b upregulation. TBR1 binds the Grin2b promoter and controls luciferase reporter expression driven by the Grin2b promoter. Pharmacological stimulation of cultured neurons, RT-PCR, immunostaining, Tbr1-deficient neurons, luciferase reporter assay with Grin2b promoter, CaMKII inhibitor (KN-93) treatment Frontiers in cellular neuroscience Medium 25309323
2010 AF9/MLLT3 suppresses TBR1 expression in postmitotic cortical neurons through interaction with DOT1L, which methylates histone H3 lysine 79 (H3K79) at the Tbr1 transcriptional start site, thereby interfering with RNA polymerase II access. AF9 also promotes cytoplasmic localization of TBR1 and its association with mitochondria. Af9 knockout mouse analysis, ChIP showing AF9 at Tbr1 TSS and H3K79 dimethylation, co-IP of AF9 with DOT1L, immunofluorescence for TBR1 localization Proceedings of the National Academy of Sciences of the United States of America High 20348416
2015 CTIP1/BCL11A directly represses Tbr1 in layer 5 neurons, which is a critical step for acquisition of the subcerebral projection fate. Conversely, lower levels of CTIP1 in layer 6 are required for TBR1 expression to direct the corticothalamic fate, establishing a dosage-dependent regulatory relationship. Mouse cortical neuron analysis, CTIP1 conditional knockout/knockdown, direct repression assay, layer-specific marker analysis The Journal of neuroscience Medium 25972180
2016 ChIP-seq shows TBR1-bound genomic regions are enriched adjacent to ASD risk genes during mouse cortical neurogenesis; seven of nine examined ASD genes are misexpressed in Tbr1 knockout cortices, including six with increased expression in deep cortical layers, supporting direct transcriptional regulation of a network of ASD genes by TBR1. ChIP-seq for TBR1 in embryonic mouse cortex, RNA-seq in Tbr1 knockout cortex, bioinformatics enrichment analysis Genome research High 27325115
2017 TBR1 has cytoplasmic/dendritic distribution in postnatal and adult rodent brain neurons, in contrast to its nuclear localization during embryonic development. Biochemical fractionation shows cytoplasmic TBR1 is enriched in the synaptosomal fraction, indicating synaptic localization in adult brain. TBR1 transcriptional activity is enhanced via interaction with CASK. DAB staining, confocal imaging, biochemical fractionation of adult cerebral cortex and hippocampus (synaptosomal fraction isolation) Journal of chemical neuroanatomy Medium 17329080
2017 CASK interacts with TBR1 (via the T740 residue), and disruption of this interaction (CASK T740A mutation) impairs extinction of associative memory in mice without affecting acquisition, identifying CASK-TBR1 interaction as a regulator of cognitive flexibility. Co-immunoprecipitation of CASK and TBR1 from brain, generation of CASK T740A knock-in mice, behavioral assays (fear conditioning, conditioned taste aversion) Journal of psychiatry & neuroscience Medium 28234597
2017 The Microprocessor complex (DROSHA/DGCR8) directly regulates the Tbr1 transcript through evolutionarily conserved hairpin structures resembling miRNA precursors in a miRNA-independent manner, controlling TBR1-positive neuron production during corticogenesis. Conditional Dgcr8 and Dicer knockout mouse cortex comparison, phenotypic analysis of TBR1-positive neurons, transcript analysis EMBO reports Medium 28232627
2018 TBR1 regulates layer 6 cortical neuron properties including dendritic patterning, synaptogenesis, and cell-intrinsic physiology. ChIP-seq and RNA-seq from layer 6 neurons show TBR1 directly controls transcriptional circuits including Wnt7b; restoring Wnt7b expression largely rescues synaptic deficits in Tbr1 conditional layer 6 knockout neurons. Conditional Tbr1 deletion in layer 6 neurons, ChIP-seq, RNA-seq, patch-clamp electrophysiology, viral Wnt7b rescue experiment Neuron High 30318412
2018 TBR1 is expressed in four mouse RGC types with dendrites in the outer IPL and is required for their laminar specification. Loss of Tbr1 results in dendrite elaboration in the inner IPL; misexpression in other cells retargets neurites to the outer IPL. Two transmembrane molecules, Sorcs3 and Cdh8, act as effectors of the Tbr1-controlled lamination program. Tbr1 conditional knockout in retina, ectopic Tbr1 misexpression, RGC subtype morphological analysis, identification of downstream effectors Sorcs3 and Cdh8 Nature neuroscience High 29632360
2018 Tbr1, Tbr2, and Pax6 form a direct feedforward genetic cascade with direct feedback repression in neocortical development. Each TF regulates multiple epigenetic factor genes controlling DNA methylation, histone marks, chromatin remodeling, and non-coding RNA. Specifically, Tbr1 activates Rybp and Auts2 to promote formation of non-canonical Polycomb repressive complex 1 (PRC1). ChIP-seq for Pax6, Tbr2, and Tbr1 in embryonic mouse neocortex, gene expression microarrays in TF mutant cortices, in situ hybridization Frontiers in neuroscience High 30186101
2018 TBR1 interacts with BCL11A, a transcription factor implicated in neurodevelopmental syndrome. Functional analyses of ASD-associated T-box missense variants reveal that only some disrupt protein function (subcellular localization, transcriptional activity, protein interactions); not all in silico-predicted deleterious variants cause functional disruption. Functional assays in transfected cells: subcellular localization, transcriptional activity, BRET-based protein interaction assays for BCL11A Scientific reports Medium 30250039
2019 The TBR1-K228E mutation (which abolishes DNA binding) causes upregulation of TBR1-K228E protein levels, altered cortical distribution of parvalbumin-positive interneurons (lower superficial, higher deep layers), and increased inhibitory synaptic transmission in layer 6 pyramidal neurons. Knock-in mouse with K228E mutation, RNA-seq, immunostaining, whole-cell patch-clamp electrophysiology Frontiers in molecular neuroscience Medium 31680851
2019 TBR1 is required for the formation and maintenance of orientation-selective J-RGCs and a group of OFF-sustained RGCs in the mouse retina. Genetic ablation of Tbr1 prevents development of these two RGC groups; ectopic Tbr1 expression in M4 ipRGCs alters dendritic branching and density but not IPL stratification level. Tbr1 retina-specific knockout, ectopic Tbr1 expression in M4 ipRGCs, morphological and functional RGC subtype analysis Cell reports Medium 30995485
2020 Tbr1 conditional knockout and heterozygous mutants have immature dendritic spines, reduced synaptic density, and reduced thalamic axonal arborization. Tbr1 regulates expression of Kif1a and Wnt7b. LiCl and a GSK3β inhibitor (WNT-signaling agonists) robustly rescue dendritic spine, synaptic, and axonal defects in Tbr1 mutant corticothalamic neurons. Tbr1 conditional knockout mice, dendritic spine morphometry, synapse density quantification, pharmacological rescue with LiCl and GSK3β inhibitor, axonal arborization analysis Cell reports High 32294447
2022 Adult Tbr1 conditional knockout mutants (in layers 5/6) have dendritic spine and synaptic deficits and reduced frequency of mEPSCs and mIPSCs. LiCl treatment robustly rescues dendritic spine maturation, synaptic defects, and both excitatory and inhibitory synaptic transmission deficits in adult mutants. Adult conditional Tbr1 KO, whole-cell patch-clamp (mEPSC/mIPSC recording), dendritic spine analysis, LiCl pharmacological rescue Journal of neurodevelopmental disorders Medium 35123407
2022 Different patient-specific Tbr1 mutations produce distinct cortical phenotypes: frameshift A136PfsX80 reduces TBR1 protein similar to KO; missense K228E causes TBR1 upregulation. Homozygous KO and A136fs show similar CUX1+ and CTIP2+ layering defects, while K228E homozygosity produces distinct layering defects. All heterozygous Tbr1 mutation types (KO, A136fs, K228E) converge on anterior commissure reduction. Multiple Tbr1 patient-specific knock-in mouse lines, cortical layer marker immunostaining, apoptosis analysis, brain structure quantification The Journal of neuroscience Medium 35944998
2023 TBR1 interactome identified ~250 putative interaction partners by affinity purification-mass spectrometry, including CASK, transcription factors, chromatin modifiers, and ASD/ID-related proteins. Five candidates (including known interactors) were validated by BRET assays. NDD-associated TBR1 variants disrupt specific protein interactions, and two distinct protein-binding domains of TBR1 are identified as essential for protein-protein interactions. Affinity purification coupled to mass spectrometry (AP-MS), bioluminescence resonance energy transfer (BRET) assays for interaction validation, functional testing of NDD variants Human molecular genetics High 36579832
2023 Pou4f1 directly binds Tbr1 at an evolutionarily conserved region in exon 6 and an intergenic region downstream of the 3'UTR (shown by CUT&Tag), and is required for Tbr1 expression in J-RGCs. Pou4f1 also directly binds Jam2 and is required for Jam2 expression, establishing a Pou4f1→Tbr1→Jam2 genetic hierarchy for J-RGC formation. CUT&Tag chromatin binding assay, Pou4f1 conditional knockout, reporter assay for enhancer activity in J-RGCs Frontiers in ophthalmology Medium 38469155
2025 The TBR1 T-box domain binds its cognate T-box binding element (TBE) in a sequence-specific, enthalpically driven, entropically opposed manner. Single-molecule FRET shows a single TBE recruits one TBR1 monomer stably, while a palindromic arrangement of two TBEs can recruit a second monomer and exhibits dynamic short-range transitions (sliding) of a monomer before dissociation or arrival of a second monomer, enabling dual occupancy. Single-molecule FRET (smFRET), isothermal titration calorimetry, molecular docking and molecular dynamics simulations Journal of molecular biology High 41237949
2025 In keratocyte-specific Tbr1 knockout mice, loss of Tbr1 causes progressive corneal stromal thinning via increased Cathepsin B expression and enhanced ECM degradation. Smad4 deficiency in Tbr1 KO (double KO) ameliorates the phenotype and normalizes Cathepsin B levels, placing Tbr1 upstream of Smad4-dependent ECM homeostasis in corneal keratocytes. Keratocyte-specific inducible knockout of Tbr1, Smad4, and double KO mice; OCT corneal thickness measurement; collagen staining; Cathepsin B immunostaining; Cathepsin B inhibitor (CA-074Me) eyedrop treatment The ocular surface Medium 39894408

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 1069 15634788
2000 Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6, and Tbr-1. The Journal of comparative neurology 760 10906711
2010 Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex. Proceedings of the National Academy of Sciences of the United States of America 267 20615956
2011 Tbr1 and Fezf2 regulate alternate corticofugal neuronal identities during neocortical development. The Journal of neuroscience : the official journal of the Society for Neuroscience 207 21228164
2011 TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract. Proceedings of the National Academy of Sciences of the United States of America 163 21285371
2014 Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nature neuroscience 149 24441682
2004 Expression of the genes Emx1, Tbr1, and Eomes (Tbr2) in the telencephalon of Xenopus laevis confirms the existence of a ventral pallial division in all tetrapods. The Journal of comparative neurology 118 15174073
2014 De novo TBR1 mutations in sporadic autism disrupt protein functions. Nature communications 100 25232744
2018 Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity. Neuron 85 30318412
2008 Progressive loss of PAX6, TBR2, NEUROD and TBR1 mRNA gradients correlates with translocation of EMX2 to the cortical plate during human cortical development. The European journal of neuroscience 61 18973570
2016 TBR1 regulates autism risk genes in the developing neocortex. Genome research 56 27325115
2010 Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America 52 20348416
2018 Tbr1 instructs laminar patterning of retinal ganglion cell dendrites. Nature neuroscience 51 29632360
2014 Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain. Frontiers in cellular neuroscience 49 25309323
2015 The Specification of Cortical Subcerebral Projection Neurons Depends on the Direct Repression of TBR1 by CTIP1/BCL11a. The Journal of neuroscience : the official journal of the Society for Neuroscience 48 25972180
2014 TBR1 is the candidate gene for intellectual disability in patients with a 2q24.2 interstitial deletion. American journal of medical genetics. Part A 45 24458984
2020 Enhancing WNT Signaling Restores Cortical Neuronal Spine Maturation and Synaptogenesis in Tbr1 Mutants. Cell reports 42 32294447
2017 MicroRNA-independent functions of DGCR8 are essential for neocortical development and TBR1 expression. EMBO reports 42 28232627
2019 Haploinsufficiency of autism causative gene Tbr1 impairs olfactory discrimination and neuronal activation of the olfactory system in mice. Molecular autism 41 30792833
2010 The T-box brain 1 (Tbr1) transcription factor inhibits astrocyte formation in the olfactory bulb and regulates neural stem cell fate. Molecular and cellular neurosciences 41 20807572
2013 Pax6 regulates Tbr1 and Tbr2 expressions in olfactory bulb mitral cells. Molecular and cellular neurosciences 36 23353076
2018 The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6→ Tbr2→ Tbr1. Frontiers in neuroscience 32 30186101
2012 Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions. Molecular syndromology 30 23112752
2019 A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice. Frontiers in molecular neuroscience 27 31680851
2020 De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature. European journal of human genetics : EJHG 26 32005960
2006 A unique subpopulation of Tbr1-expressing deep layer neurons in the developing cerebral cortex. Molecular and cellular neurosciences 26 16858776
2017 Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice. Journal of psychiatry & neuroscience : JPN 24 28234597
2022 Tbr1 Misexpression Alters Neuronal Development in the Cerebral Cortex. Molecular neurobiology 23 35781633
2022 Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1+/- mouse model of autism spectrum disorders. Molecular autism 21 35303947
2018 Functional characterization of TBR1 variants in neurodevelopmental disorder. Scientific reports 21 30250039
2020 Longitudinal developmental analysis of prethalamic eminence derivatives in the chick by mapping of Tbr1 in situ expression. Brain structure & function 20 31901976
2018 Mutations in TBR1 gene leads to cortical malformations and intellectual disability. European journal of medical genetics 20 30268909
2019 Essential Roles of Tbr1 in the Formation and Maintenance of the Orientation-Selective J-RGCs and a Group of OFF-Sustained RGCs in Mouse. Cell reports 19 30995485
2017 The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum. European journal of medical genetics 18 29288087
2016 N-acetylcysteine attenuates lipopolysaccharide-induced impairment in lamination of Ctip2-and Tbr1- expressing cortical neurons in the developing rat fetal brain. Scientific reports 18 27577752
2016 Maternal deprivation alters expression of neural maturation gene tbr1 in the amygdala paralaminar nucleus in infant female macaques. Developmental psychobiology 18 27917473
2007 Cytoplasmic distribution of T-box transcription factor Tbr-1 in adult rodent brain. Journal of chemical neuroanatomy 17 17329080
2002 Amphi-Eomes/Tbr1: an amphioxus cognate of vertebrate Eomesodermin and T-Brain1 genes whose expression reveals evolutionarily distinct domain in amphioxus development. The Journal of experimental zoology 17 12210114
2005 A unique subpopulation of Tbr1-expressing deep layer neurons in the developing cerebral cortex. Molecular and cellular neurosciences 16 16188453
2023 Exosomal miR-23a-3p derived from human umbilical cord mesenchymal stem cells promotes remyelination in central nervous system demyelinating diseases by targeting Tbr1/Wnt pathway. The Journal of biological chemistry 13 37995941
2013 Trypanosoma evansi: detection of Trypanosoma evansi DNA in naturally and experimentally infected animals using TBR(1) & TBR(2) primers. Experimental parasitology 11 23454630
2022 Shared and Distinct Functional Effects of Patient-Specific Tbr1 Mutations on Cortical Development. The Journal of neuroscience : the official journal of the Society for Neuroscience 9 35944998
2024 Deep brain stimulation of the Tbr1-deficient mouse model of autism spectrum disorder at the basolateral amygdala alters amygdalar connectivity, whole-brain synchronization, and social behaviors. PLoS biology 8 39012916
2021 Quail-chick grafting experiments corroborate that Tbr1-positive eminential prethalamic neurons migrate along three streams into hypothalamus, subpallium and septocommissural areas. Brain structure & function 8 33544184
2000 Genomic organization, sequence and chromosomal localization of the mouse Tbr2 gene and a comparative study with Tbr1. Gene 8 10974533
2023 Characterization of the TBR1 interactome: variants associated with neurodevelopmental disorders disrupt novel protein interactions. Human molecular genetics 6 36579832
2020 A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability. Human genomics 6 32948248
2023 Pou4f1-Tbr1 transcriptional cascade controls the formation of Jam2-expressing retinal ganglion cells. Frontiers in ophthalmology 4 38469155
2022 LiCl treatment leads to long-term restoration of spine maturation and synaptogenesis in adult Tbr1 mutants. Journal of neurodevelopmental disorders 3 35123407
2021 [Identification of a novel TBR1 gene variant in a Chinese pedigree affected with intellectual developmental disorder with autism and speech delay]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 3 34625926
2015 Distinct calcium signals in developing cortical interneurons persist despite disorganization of cortex by Tbr1 KO. Developmental neurobiology 3 26473411
2021 Prenatal diagnosis by whole exome sequencing in a family with a novel TBR1 mutation causing intellectual disability. Taiwanese journal of obstetrics & gynecology 2 34794744
2025 Smad4 deficiency ameliorates the progressive corneal stroma thinning caused by the loss of Tbr1. The ocular surface 1 39894408
2025 Novel TBR1 c.1303C>T Variant Led to Diagnosis of Intellectual Developmental Disorder with Autism and Speech Delay: Application of Comprehensive Family-Based Whole-Genome Analysis. Genes 1 40004448
2024 [Analysis of a child featuring global developmental delay and autism due to variant of TBR1 gene and a literature review]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 38448025
2024 Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development. Autism research : official journal of the International Society for Autism Research 1 39548698
2025 Molecular Insights Into the Binding Dynamics of Transcription Factor TBR1 to T-box DNA Sequences. Journal of molecular biology 0 41237949
2024 Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development. bioRxiv : the preprint server for biology 0 38617321

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