TBR1

This is a good article. Click here for more information.
Source: Wikipedia, the free encyclopedia.

TBR1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_006593

NM_009322

RefSeq (protein)

NP_006584

NP_033348

Location (UCSC)Chr 2: 161.42 – 161.43 MbChr 2: 61.63 – 61.64 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

T-box, brain, 1 is a

autism spectrum disorder
(ASD).

Discovery

TBR1 was identified in 1995 by the Nina Ireland Laboratory of Developmental Neurobiology Center at the

Brachyury protein, a T-box transcription factor, which plays a role in establishing symmetry during embryonic development. Thus, due to its relation to T-box genes (such as Tbx-1, Tbx-2, Tbx-3), TES-56 was renamed TBR1.[6]

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

GABA.[8] The transition from radial glial cells to postmitotic projection neurons occurs in three steps, each associated with one of the aforementioned transcription factors. The first starts out with the expression of Pax6 in radial glial cells found primarily at the ventricular surface. In the next step, Pax6 is downregulated and Tbr2 is expressed as the cell differentiates into an intermediate progenitor cell. Likewise, in the final step, Tbr2 is extremely downregulated to undetectable levels as Tbr1 signals the transition into a postmitotic projection neuron.[9]

Modulation of NMDAR

In cultured

promoter region.[10] Tbr1 is a transcriptional regulator of NR1, an essential subunit of NMDA receptors.[11]

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

RELN, which encodes the Reln protein that forms part of the extracellular matrix of cells. Thus, through regulation of Reln expression, Tbr1 regulates the formation of the matrix through which neurons migrate. Without Tbr1, neurons fail to migrate properly.[8]

Tissue and cellular distribution

Corticogenesis in wild-type mice. Similar neuronal migration occurs in humans in the development of the six-layered cerebral cortex.

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

Orthologs
of the human TBR1 gene have been identified in chimpanzee, dog, cow, rat, mouse, and zebrafish.

Corticogenesis in reeler mutant mice. Tbr-1 mutation results in similar abnormalities in cortical migration through reduction of Reelin expression.

Mice

In mice, TBR1 has been found to function in development of the brain, eye,

Cajal-Retzius cells of the marginal zone.[12]

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

cDNA clones from zebrafish were acquired by screening a zebrafish embryo using a phosphorus labeled probe. The TBR1 found in zebrafish (zf-TBR1) has 83-97% amino acid identity to orthologs in humans (hu-TBR1), xenopus (x-EOMES), and mice (mu-TBR1). The zebrafish TBR1 is only expressed in the forebrain, not in other regions of the zebrafish embryo.[14]

Lancelets

The

lancelets. A T-box-containing cDNA was isolated in the lancelet Branchiostoma belcheri and found to possess a T-domain orthologous to that of the T-Brain subfamily of T-box genes, specifically TBR1.[15] However, lancelets lack a true brain and no TBR1 transcripts were found in the neural tissue of the lancelet.[15] This suggests that the neuronal role of TBR1 evolved in vertebrates after the lancelet lineage had already diverged from that of vertebrates.[6][15]

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

autism.[17][18] Auts2 is a target of the transcription factor, TBR1, in the neocortex.[16] TBR1 is involved in both the binding and activation of the Auts2 gene.[16]

Co-regulatory proteins

Tbr1 forms a complex with CASK and regulates gene expression in cortical development. Tbr1 binds to the

C-terminal domain of Tbr1 in crucial and solely capable of this process.[7] Through luciferase reporter assays of neurons in the hippocampus, it was found that increased Tbr1/CASK complex expression results in enhanced promoter activity in genes downstream of TBR1 such as NMDAR subunit 2b (NMDAR2b), glycine transporter, interleukin-7 receptor (IL-7R) and OX-2 genes. NMDAR2b experienced the greatest change in activity.[11]

Tbr1 and CASK also play an important role in activation of the RELN gene. One study suggests that CASK acts as a

coactivator of TBR1, interacting with CINAP (CASK-interacting nucleosome assembly protein) to form a complex with Tbr1. The Tbr1/CASK/CINAP complex regulates expression of NMDAR2b and RELN, which both play important roles in long-term potentiation.[19]

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

amyloid precursor protein (APP) in neuronal migration and linkage to these diseases.[21]

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

GABA neuron migration from the basal to the dorsal forebrain and radial neuron migration in the dorsal forebrain. This exposure also decreased TBR1 and TBR2 expression. However, further research showed that cocaine exposure only delayed TBR1 expression and did not cause permanent downregulation. Therefore, in models of prenatal cocaine exposure both migration and maturation of these progenitor cells is delayed.[23]

TBR1 is also used in

telencephalon injury implicates the normal function of these cells in this region of the brain.[24]

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

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136535 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000035033 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b c d "Entrez Gene: T-box, brain, 1". Retrieved 2011-11-01.
  6. ^
    PMID 7619531
    .
  7. ^ .
  8. ^ .
  9. .
  10. .
  11. ^ .
  12. ^ 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.
  13. ^
    PMID 21285371
    .
  14. .
  15. ^ .
  16. ^ .
  17. .
  18. .
  19. .
  20. ^ .
  21. .
  22. .
  23. .
  24. .
  25. .

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

This page is based on the copyrighted Wikipedia article: TBR1. Articles is available under the CC BY-SA 3.0 license; additional terms may apply.Privacy Policy