T-box, brain, 1 is a transcription factor protein important in vertebrate embryo development. It is encoded by the TBR1 gene. This gene is also known by several other names: T-Brain 1, TBR-1, TES-56, and MGC141978. TBR1 is a member of the TBR1 subfamily of T-box family transcription factors, which share a common DNA-binding domain. Other members of the TBR1 subfamily include EOMES and TBX21. TBR1 is involved in the differentiation and migration of neurons and is required for normal brain development. TBR1 interacts with various genes and proteins in order to regulate cortical development, specifically within layer VI of the developing six-layered human cortex. Studies show that TBR1 may play a role in major neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and autism spectrum disorder (ASD).
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 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 TBR1.
Human TBR1 gene and encoded protein The human TBR1 gene is located on the q arm of the positive strand of chromosome 2. It is 8,954 base pairs in length. TBR1 is one of the three genes that make up the TBR1 subfamily of T-box genes. The two other genes that form the TBR1 subfamily are EOMES (also known as TBR2) and TBX21 (also known as T-BET). TBR1 is also known as T-box Brain Protein, T-Brain 1, and TES-56. The encoded protein consists of 682 amino acid residues and has a predicted molecular weight of 74,053 Da. It is composed of 6 exons.
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. 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 Pax6 and Tbr2, has a role in glutamatergic projection neuron differentiation. Glutamatergic neurons make and release in an activity-dependent manner the excitatory neurotransmitter glutamate as opposed to the inhibitory neurotransmitter GABA. 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 (NR2b) by acting on its promoter region. Tbr1 is a transcriptional regulator of NR1, an essential subunit of NMDA receptors.
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.
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. 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. No Tbr1 expression has been observed in the ventricular zone. Other regions of Tbr1 expression are: the olfactory bulbs and olfactory nuclei, the lateral hypothalamus region, the entopeduncular nucleus, the eminentia thalami.
Non-human orthologs Orthologs of the human TBR1 gene have been identified in chimpanzee, dog, cow, rat, mouse, and zebrafish.
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