TBR1
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Location (UCSC) | Chr 2: 161.42 – 161.43 Mb | Chr 2: 61.63 – 61.64 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
T-box, brain, 1 is a
Discovery
TBR1 was identified in 1995 by the Nina Ireland Laboratory of Developmental Neurobiology Center at the
Human TBR1 gene and encoded protein
The human TBR1 gene is located on the q arm of the positive strand of
Functions
Tbr1 is a protein, called a transcription factor, that binds to DNA and regulates the transcription of genes into mRNA. It is expressed in postmitotic projection neurons and is critical for normal brain development. Tbr1 has been shown to be expressed in the developing olfactory bulb. Tbr1 has also been observed in the developing cerebral cortex.[6]
Tbr1 has several functions. These include involvement in the developmental process, brain development, neuronal differentiation, axon guidance, and regulation of neurons in the developing neocortex.
Neuronal differentiation
Tbr1, along with
Modulation of NMDAR
In cultured
Axon guidance
Cells that stop dividing (post-mitotic) and differentiate into neurons early in cortical development are important in laying the groundwork on which other developing neurons can be guided to their proper destination. Tbr1 aids in neuronal migration in the early development of the cerebral cortex. It is largely expressed in post-mitotic neurons of the preplate, which forms a foundation upon which neurons are able to grow and move. As a transcription factor, Tbr1 modulates the expression of
Tissue and cellular distribution
Being a transcription factor, a protein that binds to specific DNA sites and thereby regulates the activity of specific genes, Tbr1 is localized in the nucleus where the cell’s DNA is located. Tbr1 is expressed in glutamergic neurons rather than GABAergic neurons.[8]
Tbr1 is expressed mainly in early-born postmitotic neurons of the developing cerebral cortex—in particular, the preplate and layer VI neurons. The preplate forms the architectural network of neurons that help developing neurons migrate. Successive migrations of neurons divide the preplate such that its inner cells form the cortical plate while its outer cells form the marginal zone. The cortical plate and the marginal zone eventually develop into six cortical layers, known as the neocortex, present in the mature cerebral cortex. These layers are numbered I-VI with layer VI being the deepest and forming first, while the remaining layers grow outward from it (from V to I). Layers II-VI develop from the cortical plate and layer I forms from the marginal zone. The subplate, intermediate zone, subventricular zone, and ventricular zone are found progressively deeper to these developing cortical layers. High expression of Tbr1 is seen in the marginal zone, cortical plate, and subplate of the developing cortex whereas little expression is seen in the subventricular zone.[8] No Tbr1 expression has been observed in the ventricular zone.[8]
Other regions of Tbr1 expression are: the olfactory bulbs and olfactory nuclei, the lateral hypothalamus region, the entopeduncular nucleus, the eminentia thalami.[8]
Non-human orthologs
Mice
In mice, TBR1 has been found to function in development of the brain, eye,
Other studies in mice have found that TBR1 is a repressor or Fezf2. It has also been found to negatively regulate corticospinal tract formation.[13]
Zebrafish
Studies in the
Lancelets
The
Gene regulation
TBR1 both positively and negatively regulates gene expression in postmitotic neurons.[16]
Genes regulated by TBR1
Fezf2 is a gene that is regulated by TBR1. Fezf2 expression is observed in layer V of the cerebral cortex. The cerebral cortex is constructed in six layers. Fezf2 expression is restricted to layer V for proper development and migration of neurons of the corticospinal tract, which is derived from layer V neurons and is involved in voluntary muscular control. Recent studies show that TBR1, expressed in layer VI, binds directly to the Fezf2 gene, preventing Fezf2 expression in layer VI. In this manner, TBR1 acts as a transcription repressor of Fezf2.[13] Mutation of TBR1 results in Fezf2 expression in layer VI and malformation of the corticospinal tract. Abnormal activation of TBR1 in layer V eliminates corticospinal tract formation.[13]
Bhlhb5 is a gene marker in the mouse brain, which is involved in differentiation of caudal identity in layer V neurons of the developing cortex, and is regulated by TBR1. It is expressed at high levels in caudal regions, but is not generally observed in the frontal cortex. Tbr1 is expressed at very high levels in the frontal cortex and very lower levels in the caudal regions. Using tbr1 null mutants, it was found that Bhlhb5 is up-regulated in the absence of TBR1. This up-regulation of Bhlhb5 led to the conclusion that tbr1 suppresses caudal identity while promoting frontal identity.[16]
The gene Auts2 is also regulated by TBR1. The autism susceptibility candidate 2 gene (Auts2) is a marker of frontal identity in the developing cortex and has been linked to
Co-regulatory proteins
Tbr1 forms a complex with CASK and regulates gene expression in cortical development. Tbr1 binds to the
Tbr1 and CASK also play an important role in activation of the RELN gene. One study suggests that CASK acts as a
Sox5 is another co-regulatory protein of Tbr1. Sox5 is a marker of layer VI neurons in the neocortex. It aids in the suppression of layer V neuron identity within layer VI cortical neurons through suppression of Fezf2. TBR1 is involved in the downstream regulation of Sox5. Sox5 expression was reduced in Tbr1 null mutants.[16] It has been found that Sox5 interacts with Tbr1 to regulate Fezf2 transcription in layer VI cortical neurons.[13][16]
Transcription factors that regulate the expression of Tbr1
Studies suggest that the Af9 protein acts as a repressor of Tbr1 in the upper layers of the six-layer developing cerebral cortex, thereby confining Tbr1 to the lower cortical layers (preplate, subplate, layer VI). This process is regulated through interaction of Af9 with the methyltransferase DOT1L, which methylates histone H3 lysine 79 (H3K79). Af9 association with DOT1L enhances methylation of H3K79 at the TBR1 transcription start site, thereby interfering with RNA polymerase II (RNAPolII) activity and reducing TBR1 expression.[20] Mutants of Af9 experience increased dimethylation of H3K79 and increased TBR1 expression.[20]
Clinical significance
TBR1 has been implicated in alterations in the brain that may lead to
Reduced function of NMDA receptors play a role in schizophrenia. This diminished function of NMDA receptor may be correlated with the reduced expression of the NMDA receptor 2B subunit (NR2b), which has also been linked to schizophrenia. TBR1, in complex with the protein, CINAP, is responsible for regulating transcription of the NR2b gene. It was hypothesized in one 2010 study that reduced TBR1 and CINAP expression may be responsible for the reduced expression of the NR2b subunit observed in brains of postmortem schizophrenics. However, TBR1 and CINAP expression were not significantly reduced in the postmortem brains, suggesting that synthesis and processing of NR2b via TBR1 is not responsible for reduced NR2b expression in schizophrenics.[22]
TBR1 expression has been shown to be downregulated by embryonic exposure to
TBR1 is also used in
Mutations of this gene have also been reported in the tissues of medulloblastoma.[25]
Variations in this gene as well as whole gene deletions have been known to cause a disorder involving Autism Spectrum Disorder, Intellectual Disability, Epilepsy with skeletal, nervous system and brain abnormalities. It is extremely rare and as of July 2020, 40 cases have been recorded worldwide, it was first described in 2014. It has Autosomal Dominant presentation and are typically de novo but rare inherited variants have been reported.
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000136535 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035033 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d "Entrez Gene: T-box, brain, 1". Retrieved 2011-11-01.
- ^ PMID 7619531.
- ^ S2CID 4415747.
- ^ PMID 11239428.
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- ^ S2CID 14671180.
- ^ Hevner R (August 10, 2011). "TBR1: Homo sapiens T-box, brain, 1". Transcription Factor Encyclopedia: 1–4. Archived from the original on April 6, 2012. Retrieved November 2, 2011.
- ^ PMID 21285371.
- S2CID 980064.
- ^ PMID 12210114.
- ^ PMID 20615956.
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- ^ PMID 20348416.
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Further reading
- Hsueh YP, Wang TF, Yang FC, Sheng M (Mar 2000). "Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2". Nature. 404 (6775): 298–302. S2CID 4415747.
- Stefanovska AM, Efremov GD, Dimovski AJ, Jasar D, Zografski G, Josifovski T, Panovski M, Jankova R, Spiroski M (Nov 2001). "TbetaR-I(6A) polymorphism is not a tumor susceptibility allele in Macedonian colorectal cancer patients. Correspondence re: B. Pasche et al. Type I TbetaR-I(6A) Is a Candidate Tumor Susceptibility Allele. Cancer Res., 58: 2727-2732, 1998". Cancer Research. 61 (22): 8351–8352. PMID 11719470.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.