TBR1

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. 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. 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. 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 of the marginal zone. Other studies in mice have found that TBR1 is a repressor or Fezf2. It has also been found to negatively regulate corticospinal tract formation. Lancelets The evolution of TBR1 has been studied in amphioxi, also known as 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. However, lancelets lack a true brain and no TBR1 transcripts were found in the neural tissue of the lancelet. This suggests that the neuronal role of TBR1 evolved in vertebrates after the lancelet lineage had already diverged from that of vertebrates. == Gene regulation ==

TBR1 both positively and negatively regulates gene expression in postmitotic neurons. 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. 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. Auts2 is a target of the transcription factor, TBR1, in the neocortex. 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. 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. Mutants of Af9 experience increased dimethylation of H3K79 and increased TBR1 expression. == Clinical significance ==

TBR1 has been implicated in alterations in the brain that may lead to Alzheimer's disease (AD) and Parkinson's disease (PD). TBR1 expressing mice showed that cholinergic neurons of the basal forebrain (ChBF), the degeneration of which are involved in the development of AD and PD, migrate from the ventral pallium to the subpallium. This was confirmed using TBR1 null mice. In the future, the researchers plan to explore the role of amyloid precursor protein (APP) in neuronal migration and linkage to these diseases. 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. TBR1 expression has been shown to be downregulated by embryonic exposure to cocaine. Prenatal cocaine exposure in a mouse model caused a decrease in both 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. TBR1 is also used in immunohistochemical techniques in neurological research. It has been used to identify layer VI developing cortical neurons as well as 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. Mutations of this gene have also been reported in the tissues of medulloblastoma. 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 ==