Tbr1 and Fezf2 Regulate Alternate Corticofugal Neuronal Identities during Neocortical Development
Open accessAbstract
The molecular mechanisms regulating fate divergence of closely related, but distinct, layer 6 corticothalamic and layer 5 subcerebral projection neurons are largely unknown. We present evidence for central transcriptional mechanisms that regulate fate specification of corticothalamic (layer 6) and subcerebral (layer 5) projection neurons. We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2. These conclusions are based on the following: (1) In Tbr1 −/− mice, the number of cells expressing layer 6 markers was reduced, and the number of cells expressing layer 5 markers was increased. Early-born (birthdated on E11.5) neurons ectopically expressed subcerebral neuronal markers, and extended their axons into subcerebral targets. (2) Ectopic Tbr1 expression in layer 5 neurons prevented them from extending axons into the brainstem and the spinal cord. (3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene. (4) Analysis of Fezf2 mutants and Tbr1 −/− ; Fezf2 −/− compound mutants provided evidence that Fezf2 blocks corticothalamic fate in layer 5 by reducing Tbr1 expression in subcerebral neurons. All neocortical regions appear to use this core transcriptional program to specify corticothalamic (layer 6) and subcerebral (layer 5) projection neurons.
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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 [232]
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- Authors
- McKenna, W. L., Betancourt, J., Larkin, K. A., Abrams, B., Guo, C., Rubenstein, J. L. R., & Chen, B.
- Affiliations
- University of California, Santa Cruz (US)
- University of California, San Francisco (US)
- Corresponding author
- Chen, Bin
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-01-12
- Volume
- 31
- Issue
- 2
- Pages
- 549-564
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3276402
- OpenAlex
- W2092195277
- Cited by
- 252
- References
- 26
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 11 · 2023: 15 · 2022: 22 · 2021: 15 · 2020: 13 · 2019: 17 · 2018: 19 · 2017: 18 · 2016: 18 · 2015: 22 · 2014: 18 · 2013: 28 · 2012: 13
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- March of Dimes Foundation
- California Institute of Regenerative Medicine
- National Institute of General Medical Sciences (K12GM068524)
- National Institute of Neurological Disorders and Stroke (NS34661, R01NS034661, R01NS099099)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- Tbr1, Fezf2, corticothalamic neurons, layer 6, layer 5, neocortex development, neuronal fate specification, CTIP2, transcriptional regulation, axon targeting
- MeSH terms
- Animals, Axons, Brain Stem, DNA-Binding Proteins, Immunohistochemistry, Mutation, Nerve Tissue Proteins, Neurons, Protein Binding, Repressor Proteins, Spinal Cord, Thalamus, Transcription, Genetic, Mice, Knockout, Neocortex, T-Box Domain Proteins, Tumor Suppressor Proteins, Chromatin Immunoprecipitation, Mice, Neurogenesis
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