TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract
Open accessAbstract
The corticospinal (CS) tract is involved in controlling discrete voluntary skilled movements in mammals. The CS tract arises exclusively from layer (L) 5 projection neurons of the cerebral cortex, and its formation requires L5 activity of Fezf2 ( Fezl , Zfp312 ). How this L5-specific pattern of Fezf2 expression and CS axonal connectivity is established with such remarkable fidelity had remained elusive. Here we show that the transcription factor TBR1 directly binds the Fezf2 locus and represses its activity in L6 corticothalamic projection neurons to restrict the origin of the CS tract to L5. In Tbr1 null mutants, CS axons ectopically originate from L6 neurons in a Fezf2 -dependent manner. Consistently, misexpression of Tbr1 in L5 CS neurons suppresses Fezf2 expression and effectively abolishes the CS tract. Taken together, our findings show that TBR1 is a direct transcriptional repressor of Fezf2 and a negative regulator of CS tract formation that restricts the laminar origin of CS axons specifically to L5.
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PAX5 and FEZF2 are involved in transcription regulation during central nervous system development.
“PAX5 and FEZF2 are involved in transcription regulation during central nervous system development.4,24,37”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [37]
Interactions of several genes with Tbr1 determine corticothalamic projection of layer VI neurons, callosal projection of superficial cortical layer neurons, and subcortical projection of layer V neurons.
“Complex interactions of several genes with Tbr1 determine the corticothalamic projection of layer VI neurons, callosal projection of neurons in the cortical superficial layers [335] and subcortical projection of layer V neurons [50, 142, 232].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [142]
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Mapping and quantifying mammalian transcriptomes by RNA-Seq
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L., & Wold, B. (2008) · Nature Methods · doi:10.1038/nmeth.1226 · Cited by 13,696 · see citing works
Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells
Lee, T. I., Jenner, R. G., Boyer, L. A., Guenther, M. G., Levine, S. S., Kumar, R., Chevalier, B. S., Johnstone, S. E., Cole, M. F., Isono, K., et al. (2006) · Cell · doi:10.1016/j.cell.2006.02.043 · Cited by 2,238 · see citing works
A gene expression atlas of the central nervous system based on bacterial artificial chromosomes
Gong, S., Zheng, C., Doughty, M. L., Losos, K., Didkovsky, N., Schambra, U. B., Nowak, N. J., Joyner, A., Leblanc, G., Hatten, M. E., et al. (2003) · Nature · doi:10.1038/nature02033 · Cited by 2,108 · see citing works
Neuronal subtype specification in the cerebral cortex
Molyneaux, B. J., Arlotta, P., Menezes, J. R. L., & Macklis, J. D. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2151 · Cited by 1,632 · see citing works
Descending Pathways in Motor Control
Lemon, R. N. (2008) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125547 · Cited by 1,599 · see citing works
A Highly Efficient Recombineering-Based Method for Generating Conditional Knockout MutationsPreprint
Liu, P., Jenkins, N. A., & Copeland, N. G. (2003) · Genome Research · doi:10.1101/gr.749203 · Cited by 1,013 · see citing works
Sequence Variants in <i>SLITRK1</i> Are Associated with Tourette's Syndrome
Abelson, J. F., Kwan, K. Y., O'Roak, B. J., Baek, D. Y., Stillman, A. A., Morgan, T. M., Mathews, C. A., Pauls, D. L., Rašin, M.-R., Gunel, M., et al. (2005) · Science · doi:10.1126/science.1116502 · Cited by 940 · see citing works
Self-citationTbr1 regulates differentiation of the preplate and layer 6
Hevner, R. F., Shi, L., Justice, N., Hsueh, Y.-P., Sheng, M., Smiga, S., Bulfone, A., Goffinet, A. M., Campagnoni, A. T., & Rubenstein, J. L. R. (2001) · Neuron · doi:10.1016/s0896-6273(01)00211-2 · Cited by 857 · see citing works
Controlled expression of transgenes introduced by in vivo electroporation
Matsuda, T., & Cepko, C. L. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0610155104 · Cited by 666 · see citing works
Johnson, M. B., Kawasawa, Y. I., Mason, C. E., Krsnik, Ž., Coppola, G., Bogdanović, D., Geschwind, D. H., Mane, S. M., State, M. W., & Šestan, N. (2009) · Neuron · doi:10.1016/j.neuron.2009.03.027 · Cited by 603 · see citing works
Self-citationSubdivisions of primary motor cortex based on cortico-motoneuronal cells
Rathelot, J.-A., & Strick, P. (2009) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.0808362106 · Cited by 590 · see citing works
Fezl Is Required for the Birth and Specification of Corticospinal Motor Neurons
Molyneaux, B. J., Arlotta, P., Hirata, T., Hibi, M., & Macklis, J. D. (2005) · Neuron · doi:10.1016/j.neuron.2005.08.030 · Cited by 481 · see citing works
Constructing the cerebral cortex: Neurogenesis and fate determination
McConnell, S. K. (1995) · Neuron · doi:10.1016/0896-6273(95)90168-x · Cited by 416 · see citing works
Correction to: The Brachyury gene encodes a novel DNA binding protein.
Kispert, A., & Hermann, B. G. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb06179.x · Cited by 406 · see citing works
O’Leary, D. D. M., & Koester, S. E. (1993) · Neuron · doi:10.1016/0896-6273(93)90049-w · Cited by 361 · see citing works
The Corticospinal System: From Development to Motor Control
Martin, J. H. (2005) · The Neuroscientist · doi:10.1177/1073858404270843 · Cited by 358 · see citing works
Chen, B., Schaevitz, L. R., & McConnell, S. K. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0508732102 · Cited by 353 · see citing works
Kawamoto, S., Niwa, H., Tashiro, F., Sano, S., Kondoh, G., Takeda, J., Tabayashi, K., & Miyazaki, J. (2000) · FEBS Letters · doi:10.1016/s0014-5793(00)01338-7 · Cited by 351 · see citing works
Bulfone, A., Wang, F., Hevner, R. F., Anderson, S. A., Cutforth, T., Chen, S., Meneses, J. J., Pedersen, R. A., Axel, R., & Rubenstein, J. L. R. (1998) · Neuron · doi:10.1016/s0896-6273(00)80647-9 · Cited by 325 · see citing works
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Bedogni, F., Hodge, R. D., Elsen, G. E., Nelson, B. R., Daza, R. A. M., Beyer, R. P., Bammler, T. K., Rubenstein, J. L. R., & Hevner, R. F. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002285107 · Cited by 322 · see citing works
Many Paths to Synaptic Specificity
Sanes, J. R., & Yamagata, M. (2009) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.24.110707.175402 · Cited by 307 · see citing works
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Lai, T. S., Jabaudon, D., Molyneaux, B. J., Azim, E., Arlotta, P., Menezes, J. R. L., & Macklis, J. D. (2008) · Neuron · doi:10.1016/j.neuron.2007.12.023 · Cited by 300 · see citing works
Kwan, K. Y., Lam, M. M. S., Krsnik, Ž., Kawasawa, Y. I., Lefebvre, V., & Šestan, N. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806791105 · Cited by 271 · see citing works
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McKenna, W. L., Betancourt, J., Larkin, K. A., Abrams, B., Guo, C., Rubenstein, J. L. R., & Chen, B. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4131-10.2011 · Cited by 252 · see citing works
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Self-citationCatsman‐Berrevoets, C. E., & Kuypers, H. G. J. M. (1981) · Brain Research · doi:10.1016/0006-8993(81)90986-0 · Cited by 224 · see citing works
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ten Donkelaar, H. J., Lammens, M. M. Y., Wesseling, P., Hori, A., Keyser, A., & Rotteveel, J. J. (2004) · Journal of Neurology · doi:10.1007/s00415-004-0653-3 · Cited by 135 · see citing works
Donoghue, M. J., & RAKIC, P. T. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-14-05967.1999 · Cited by 128 · see citing works
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Iwasato, T., Nomura, R., Ando, R., Ikeda, T., Tanaka, M., & Itohara, S. (2004) · genesis · doi:10.1002/gene.20009 · Cited by 116 · see citing works
Jacobs, E. C., Campagnoni, C. W., Kampf, K., Reyes, S. D., Kalra, V., Handley, V., Xie, Y., Hong‐Hu, Y., Spreuer, V., Fisher, R. S., et al. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05258.x · Cited by 112 · see citing works
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Wang, T., Ding, C., Wang, G., Luo, S., Lin, Y., Ruan, Y., Hevner, R., Rubenstein, J. L. R., & Hsueh, Y. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02845.x · Cited by 83 · see citing works
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- Authors
- Han, W., Kwan, K. Y., Shim, S., Lam, M. M. S., Shin, Y., Xu, X., Zhu, Y., Li, M., & Šestan, N.
- Affiliations
- Yale University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-02
- Volume
- 108
- Issue
- 7
- Pages
- 3041-3046
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3041103
- OpenAlex
- W2109726419
- Cited by
- 206
- References
- 35
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 17 · 2023: 16 · 2022: 13 · 2021: 12 · 2020: 9 · 2019: 13 · 2018: 14 · 2017: 15 · 2016: 13 · 2015: 18 · 2014: 16 · 2013: 24 · 2012: 12
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- China Scholarship Council
- National Institutes of Health
- Samsung
- National Institute of Neurological Disorders and Stroke (R01NS054273, NS 054273)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Tbr1, Fezf2, corticospinal tract, transcriptional repression, transcription factor binding, axonal connectivity
- MeSH terms
- Animals, Axons, Base Sequence, DNA-Binding Proteins, Luciferases, Molecular Sequence Data, Nerve Tissue Proteins, Plasmids, Pyramidal Tracts, Sequence Analysis, DNA, Sequence Analysis, RNA, Mice, Knockout, Gene Expression Regulation, Developmental, Reverse Transcriptase Polymerase Chain Reaction, T-Box Domain Proteins, Chromatin Immunoprecipitation, Mice
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