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Gene Review

Tbr1  -  T-box brain gene 1

Mus musculus

Synonyms: T-box brain protein 1, T-brain-1, TBR-1, TES-56
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High impact information on Tbr1

  • CASK acts as a coactivator of Tbr-1 to induce transcription of T-element containing genes, including reelin, a gene that is essential for cerebrocortical development [1].
  • CASK enters the nucleus and binds to a specific DNA sequence (the T-element) in a complex with Tbr-1 [1].
  • This study suggests that reduction of the CINAP protein level by synaptic stimulation contributes to regulation of the transcriptional activity of the Tbr-1/CASK/CINAP protein complex and thus modifies expression of the NR2b gene [2].
  • CASK acts as a coactivator for Tbr-1, an essential transcription factor in cerebral cortex development [2].
  • Mice bearing a P2-IRES-tau-lacZ allele and deficient in either Tbr-1 or Dlx-1/Dlx-2 reveal the convergence of axons to one medial and one lateral site at positions analogous to those observed in wild-type mice [3].

Biological context of Tbr1

  • Studies in Tbr1 mutant mice suggested that Tbr1 plays a role in DCN morphogenesis but is not required for reelin expression, glutamatergic differentiation, or the initial formation of efferent axon pathways [4].
  • Tbr1 is broadly expressed in both lateral and ventral pallial histogenetic divisions (the lateroventral migratory stream plus the mantle) during early and intermediate embryonic development; its signal becomes weak in parts of the mantle during late embryonic development [5].
  • Here we report the cloning of chicken Tbr1 and of murine and chicken Tbr2 (orthologs of the Xenopus eomesodermin gene), the mapping of the murine Tbr2 to chromosome 9, and their pattern of expression during mouse and chick embryogenesis [6].
  • The subsequent transition from intermediate progenitor cell to postmitotic neuron is marked by downregulation of Tbr2 and upregulation of Tbr1, another T-domain transcription factor [7].
  • On the contrary, there were eight HNF-3beta binding sites in the Tbr1 gene promoter but only three in the Tbr2 promoter [8].

Anatomical context of Tbr1

  • Surprisingly, thalamic axons (which do not express Tbr1) deviated into the external capsule and amygdala regions, without entering the cortex [9].
  • In Tbr1 mutants, cortical pioneer axons entered the subpallium at the appropriate time, but most stopped growing without entering the diencephalon [9].
  • To test this hypothesis, the development of corticothalamic and thalamocortical connections was studied in mice with mutations of transcription factor genes expressed specifically in the cortex (Tbr1), the dorsal thalamus (Gbx2), or both (Pax6) [9].
  • The expression of Tbr1 (Neuron 15 (1995) 63) and Tbr2 (Mech Dev 84 (1999) 133) have virtually identical onset, at around E10.5, and expression domains in the mouse telencephalon [10].
  • A unique subpopulation of Tbr1-expressing deep layer neurons in the developing cerebral cortex [11].

Regulatory relationships of Tbr1

  • This transcription factor sequence is modified in preplate neurons, in which Tbr2 is transiently coexpressed with Tbr1, and in the direct differentiation pathway from radial glia --> postmitotic projection neuron, in which Tbr2 is expressed briefly or not at all [7].
  • In contrast, misexpression of Zfp312 in cortically projecting pyramidal neurons of layers II and III induced the expression of Tbr1, a transcription factor enriched in deep-layer neurons, and the formation of ectopic subcortical axonal projections [12].

Other interactions of Tbr1

  • Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: evidence that cortical and thalamic axons interact and guide each other [9].
  • 5. Tbr1(+) cells in the marginal zone were almost always reelin(+) [13].
  • Earlier studies allowed the identification of five mouse T-box genes, T, Tbx1-3, and Tbr1, that all map to different chromosomal locations and are expressed in unique temporal and spatial patterns during embryogenesis [14].
  • Similarly, both RNA and protein expression levels of NMDAR subunit 1 (NR1), which also contains the non-palindromic T-elements in its 5' regulatory region, were reduced in Tbr-1 knockout mice [15].
  • Differences in the expression topography of Tbr-1 and Emx-1 suggest the existence of a novel "ventral pallium" subdivision, which is an Emx-1-negative pallial territory intercalated between the striatum and the lateral pallium [16].

Analytical, diagnostic and therapeutic context of Tbr1

  • In situ hybridizations revealed that ccp1 was expressed in the cortical plate between Reelin and Tbr1-positive layers in the dorsal cortex at E15 [17].


  1. Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Hsueh, Y.P., Wang, T.F., Yang, F.C., Sheng, M. Nature (2000) [Pubmed]
  2. Transcriptional modification by a CASK-interacting nucleosome assembly protein. Wang, G.S., Hong, C.J., Yen, T.Y., Huang, H.Y., Ou, Y., Huang, T.N., Jung, W.G., Kuo, T.Y., Sheng, M., Wang, T.F., Hsueh, Y.P. Neuron (2004) [Pubmed]
  3. An olfactory sensory map develops in the absence of normal projection neurons or GABAergic interneurons. Bulfone, A., Wang, F., Hevner, R., Anderson, S., Cutforth, T., Chen, S., Meneses, J., Pedersen, R., Axel, R., Rubenstein, J.L. Neuron (1998) [Pubmed]
  4. Development of the deep cerebellar nuclei: transcription factors and cell migration from the rhombic lip. Fink, A.J., Englund, C., Daza, R.A., Pham, D., Lau, C., Nivison, M., Kowalczyk, T., Hevner, R.F. J. Neurosci. (2006) [Pubmed]
  5. Expression of Dbx1, Neurogenin 2, Semaphorin 5A, Cadherin 8, and Emx1 distinguish ventral and lateral pallial histogenetic divisions in the developing mouse claustroamygdaloid complex. Medina, L., Legaz, I., González, G., De Castro, F., Rubenstein, J.L., Puelles, L. J. Comp. Neurol. (2004) [Pubmed]
  6. Expression pattern of the Tbr2 (Eomesodermin) gene during mouse and chick brain development. Bulfone, A., Martinez, S., Marigo, V., Campanella, M., Basile, A., Quaderi, N., Gattuso, C., Rubenstein, J.L., Ballabio, A. Mech. Dev. (1999) [Pubmed]
  7. Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. Englund, C., Fink, A., Lau, C., Pham, D., Daza, R.A., Bulfone, A., Kowalczyk, T., Hevner, R.F. J. Neurosci. (2005) [Pubmed]
  8. Genomic organization, sequence and chromosomal localization of the mouse Tbr2 gene and a comparative study with Tbr1. Ueno, M., Kimura, N., Nakashima, K., Saito-Ohara, F., Inazawa, J., Taga, T. Gene (2000) [Pubmed]
  9. Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: evidence that cortical and thalamic axons interact and guide each other. Hevner, R.F., Miyashita-Lin, E., Rubenstein, J.L. J. Comp. Neurol. (2002) [Pubmed]
  10. Developmental expression of the T-box transcription factor T-bet/Tbx21 during mouse embryogenesis. Faedo, A., Ficara, F., Ghiani, M., Aiuti, A., Rubenstein, J.L., Bulfone, A. Mech. Dev. (2002) [Pubmed]
  11. A unique subpopulation of Tbr1-expressing deep layer neurons in the developing cerebral cortex. Kolk, S.M., Whitman, M.C., Yun, M.E., Shete, P., Donoghue, M.J. Mol. Cell. Neurosci. (2006) [Pubmed]
  12. Zfp312 is required for subcortical axonal projections and dendritic morphology of deep-layer pyramidal neurons of the cerebral cortex. Chen, J.G., Rasin, M.R., Kwan, K.Y., Sestan, N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  13. Cajal-Retzius cells in the mouse: transcription factors, neurotransmitters, and birthdays suggest a pallial origin. Hevner, R.F., Neogi, T., Englund, C., Daza, R.A., Fink, A. Brain Res. Dev. Brain Res. (2003) [Pubmed]
  14. Evolution of mouse T-box genes by tandem duplication and cluster dispersion. Agulnik, S.I., Garvey, N., Hancock, S., Ruvinsky, I., Chapman, D.L., Agulnik, I., Bollag, R., Papaioannou, V., Silver, L.M. Genetics (1996) [Pubmed]
  15. Identification of Tbr-1/CASK complex target genes in neurons. Wang, T.F., Ding, C.N., Wang, G.S., Luo, S.C., Lin, Y.L., Ruan, Y., Hevner, R., Rubenstein, J.L., Hsueh, Y.P. J. Neurochem. (2004) [Pubmed]
  16. 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. Puelles, L., Kuwana, E., Puelles, E., Bulfone, A., Shimamura, K., Keleher, J., Smiga, S., Rubenstein, J.L. J. Comp. Neurol. (2000) [Pubmed]
  17. Expression of coiled-coil protein 1, a novel gene downstream of FGF2, in the developing brain. Pellicano, F., Inglis-Broadgate, S.L., Pante, G., Ansorge, W., Iwata, T. Gene Expr. Patterns (2006) [Pubmed]
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