User:Tas45/TBR1

T-box brain protein 1, TBR1, is a protein that is encoded by the TBR-1 gene. This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978.

Genomics

The TBR1 gene is locate on the q arm of the positive strand of chromosome 2. It is 8,954 base pairs in length. The encoded protein consists of 682 amino acids and has a predicted molecular weight of 74,053 Da. It is composed of 6 exons.

Definition

TBR1 is one of the three genes that make up the TBR1 subfamily of T-box genes. TBR1 is also known as T-box Brain Protein, T-Brain 1, and TES-56. It is a transcription factor expressed in postmitotic projection neurons and is critical for normal brain development. The two other genes that form the TBR1 family and closely interact with TBR1 are EOMES (also known as TBR2) and TBX21 (also known as T-BET). All three of these genes have been shown to be expressed in the developing olfactory bulb. TBR1 has also been observed in the developing cerebral cortex.

Function

TBR1 has several functions. These include involvement in the developmental process, brain development, neuronal differentiation, and regulation of neurons in the developing neocortex.

Neuron Differentiation

Tbr1, along with Pax6 and Tbr2, has a role in glutamatergic projection neuron differentiation. 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.

Modulation of NMDAR

In cultured hippocampal neurons, Tbr1 and calcium/calmodulin-dependent serine kinase (CASK) interact with CASK-interacting nucleosome assembly protein (CINAP) to modulate the expression of N-methyl-D-aspartic acid receptor subunit 2b (NMDAR2b).

Discovery

TBR1 was identified in 1995 by the Nina Ireland Laboratory of Developmental Neurobiology Center at the University of California, San Francisco. The gene, initially named Tes-56, was found to be largely expressed in the telencephalic vesicles of the developing forebrain of mice. The protein product of Tes-56 was discovered to be very homologous to 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 Tbr-1.

Localization and Regional Expression

Being a transcription factor, Tbr-1 is localized to cell nuclei.

Tbr-1 is expressed in glutamergic neurons as opposed to GABAergic neurons. Tbr-1 is expressed mainly in early-born postmitotic neurons of the developing cortex—in particular, the preplate and layer VI neurons. High expression of Tbr-1 is seen in the marginal zone, cortical plate, and subplate of the developing cortex whereas little expression is seen in the subventricular zone. No Tbr-1 expression has been observed in the ventricular zone. Other regions of Tbr-1 expression are: the olfactory bulbs and olfactory nuclei; the lateral hypothalamus region; the entopeduncular nucleus; the eminentia thalami.

Studies in Other Species

Human gene TBR1 also has an orthologous gene in zebrafish. Orthologs have also been identified in chimpanzee, dog, cow, rat, and mouse.

Mice

In mice, TBR1 has been found to function in development of the brain, eye, immune system, mesoderm, and placenta. It is also involved in glutamatergic neuronal differentiation in the developing mouse brain. It was discovered that Tbr-1 is expressed by postmitotic cortical neurons in mice and in humans. One target gene of TBR1 in the mouse brain is Reln or Reelin. Tbr-1 mutant mice have been found to have reduced Reln expression, resulting in improper neuronal migration, particularly in Cajal-Retzius cells.

Other studies in mice have found that TBR1 is a repressor or Fezf2. It has also been found to negatively regulate corticalspinal tract formation.

Lancelets

In Amphioxus, also known as Lancelets, the evolution of TBR1 has been studied. A single orthologous gene is expressed in the Lancelet.

Gene Interactions

TBR1 both positively and negatively regulates gene expression in postmitotic neurons.

CASK

Tbr-1 binds to the guanylate kinase (GK) domain of CASK. It was determined that the C-terminal domain of Tbr-1 in crucial and solely capable of this process. Through luciferase reporter assays of neurons in the hippocampus, it was found that increased Tbr-1/CASK complex expression results in enhanced promoter activity in genes downstream of Tbr-1 such as NMDAR subunit 2b (NMDAR2b), glycine transporter, interleukin 7 receptor (IL-7R) and OX-2 genes. NMDAR2b experienced the greatest change in activity.

TBR1 and CASK also play an important role in activation of the Reln gene. One study suggests that CASK, a co-activator of Tbr-1, interacts with CINAP (CASK-interacting nucleosome assembly protein) to form a complex with Tbr-1. The Tbr-1/CASK/CINAP complex regulates expression of NMDAR2b and RELN, which both play important roles in long-term potentiation.

Fezf2

The cerebral cortex is constructed in layers (6 total). 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, expression of Fezf2 expression must be restricted to layer V. Recent studies show that Tbr-1, expressed in layer VI, binds directly to the Fezf2 gene, preventing Fezf2 expression in layer VI. In this manner, Tbr-1 acts as a transcription repressor of Fezf2.

Mutation of Tbr-1 results in Fezf2 expression in layer VI and malformation of the corticospinal tract. Abnormal activation of Tbr-1 in layer V eliminates corticospinal tract formation.

Af9

Studies suggest that the Af9 protein acts as a repressor of Tbr-1 in the upper layers of the six-layer developing cerebral cortex, thereby confining Tbr-1 to the lower cortical layers 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 Tbr-1 transcription start site, thereby interfering with RNA polymerase II (RNAPolII) activity and reducing Tbr-1 expression.

Mutants of Af9 experience increased dimethylation of H3K79 and increased Tbr-1 expression.

Bhlhb5

Bhlhb5 is a gene marker in the mouse brain, which is responsible for procurement of caudal identity. 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 TBR1. This up-regulation of Bhlhb5 led to the conclusion that TBR1 suppresses caudal identity.

Sox5

Tbr1 is involved in the downstream regulation of Sox5. It is also involved in the maintenance of Sox5. It has been found that Sox5 interacts with Tbr1 to regulate Fezf2 transcription.

Auts2

Auts2 is a target of the transcription factor, TBR1 in the neocortex. TBR1 is involved in both its binding and activation of Auts2. TBR1 is necessary for Auts2 expression and is capable of inducing this.

Use in Research

Tbr1 is used in immunohistochemical techniques in neurological research. It has been used to identify the prethalamic eminence, pallium, and dorsal forebrain. The presence of Tbr1 in stem cells responding to telencephalon injury implicates the normal function of these cells in this region of the brain.

See also

• T-box family
• TBR2