View source for TBR1

{{Short description|Protein-coding gene in Homo sapiens}}
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'''T-box, brain, 1''' is a [[transcription factor]] [[protein]] important in vertebrate [[embryo]] development.  It is encoded by the ''TBR1'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: T-box, brain, 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=10716| access-date = 2011-11-01 <!-- T22:08:16.308-07:00 --> }}</ref><ref name="Bulfone">{{cite journal | vauthors = Bulfone A, Smiga SM, Shimamura K, Peterson A, Puelles L, Rubenstein JL | title = T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex | journal = Neuron | volume = 15 | issue = 1 | pages = 63–78 | date = Jul 1995 | pmid = 7619531 | doi = 10.1016/0896-6273(95)90065-9 | doi-access = free }}</ref> This gene is also known by several other names: '''''T-Brain 1''''', '''''TBR-1''''', '''''TES-56''''', and '''''MGC141978'''''.<ref name="entrez"/>  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 [[Eomesodermin|EOMES]] and [[TBX21]]. TBR1 is involved in the [[Cellular differentiation|differentiation]] and migration of [[neuron]]s and is required for normal brain development. TBR1 interacts with various genes and proteins in order to regulate [[Cerebral cortex|cortical]] development, specifically within layer VI of the developing six-layered human cortex.<ref name="Hseuh">{{cite journal | vauthors = Hsueh YP, Wang TF, Yang FC, Sheng M | title = Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2 | journal = Nature | volume = 404 | issue = 6775 | pages = 298–302 | date = Mar 2000 | pmid = 10749215 | doi = 10.1038/35005118 | bibcode = 2000Natur.404..298H | s2cid = 4415747 }}</ref> 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 [[Cerebrum|telencephalic vesicles]] of the developing [[forebrain]] of mice. The protein product of TES-56 was discovered to be [[Homology (biology)|homologous]] to the [[Brachyury|Brachyury protein]], a [[T-box]] transcription factor, which plays a role in establishing symmetry during [[embryo]]nic development. Thus, due to its relation to T-box genes (such as ''Tbx-1'', ''Tbx-2'', ''Tbx-3''), ''TES-56'' was renamed ''TBR1''.<ref name=Bulfone/>

== 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.<ref name=entrez/> ''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 ''[[Eomesodermin|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''.<ref name=Bulfone/> 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]].<ref name=entrez/>

== 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 [[G0 phase|postmitotic]] [[Pyramidal cell|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]].<ref name=Bulfone/>

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]].<ref name=Hevner/> The transition from [[radial glial cell]]s 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 [[Progenitor cell|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.<ref name="Englund">{{cite journal | vauthors = Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A, Kowalczyk T, Hevner RF | title = Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex | journal = The Journal of Neuroscience | volume = 25 | issue = 1 | pages = 247–51 | date = Jan 2005 | pmid = 15634788 | pmc = 6725189 | doi = 10.1523/JNEUROSCI.2899-04.2005 | doi-access = free }}</ref>

=== Modulation of NMDAR ===

In cultured [[hippocampal]] neurons, Tbr1 and [[CASK|calcium/calmodulin-dependent serine kinase (CASK)]] interact with CASK-interacting nucleosome assembly protein (CINAP) to modulate the expression of [[NR2B|''N''-methyl-<small>D</small>-aspartic acid receptor subunit 2b]] (NR2b) by acting on its [[promoter (biology)|promoter]] region.<ref name="pmid21576927">{{cite journal | vauthors = Chung WC, Huang TN, Hsueh YP | title = Targeted deletion of CASK-interacting nucleosome assembly protein causes higher locomotor and exploratory activities | journal = Neuro-Signals | volume = 19 | issue = 3 | pages = 128–41 | year = 2011 | pmid = 21576927 | doi = 10.1159/000327819 | doi-access = free }}</ref>  Tbr1 is a transcriptional regulator of NR1, an essential subunit of [[NMDA receptor]]s.<ref name="Wang T"/>

=== 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.<ref name="Hevner"/>

== Tissue and cellular distribution ==
[[File:Corticogenesis in a wild-type mouse with captions in english copy.png|thumb|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.<ref name=Hevner/>

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.<ref name="Hevner"/> No Tbr1 expression has been observed in the ventricular zone.<ref name="Hevner">{{cite journal | vauthors = Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M, Smiga S, Bulfone A, Goffinet AM, Campagnoni AT, Rubenstein JL | title = Tbr1 regulates differentiation of the preplate and layer 6 | journal = Neuron | volume = 29 | issue = 2 | pages = 353–66 | date = Feb 2001 | pmid = 11239428 | doi = 10.1016/S0896-6273(01)00211-2 | doi-access = free }}</ref>

Other regions of Tbr1 expression are: the olfactory bulbs and olfactory nuclei, the [[lateral hypothalamus]] region, the entopeduncular nucleus, the eminentia thalami.<ref name=Hevner/>

== Non-human orthologs ==
[[Ortholog]]s of the human ''TBR1'' gene have been identified in chimpanzee, dog, cow, rat, mouse, and zebrafish.
[[File:Corticogenesis in reeler mutant mouse with captions in english.png|thumb|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, [[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.<ref name="Hevner2">{{cite journal |last1=Hevner |first1=Robert |title=TBR1: ''Homo sapiens'' T-box, brain, 1 |journal=[[Transcription Factor Encyclopedia]] |pages=1–4 |date=August 10, 2011 |url=http://www.cisreg.ca/cgi-bin/tfe/articles.pl?tfid=156 |access-date=November 2, 2011 |archive-date=April 6, 2012 |archive-url=https://web.archive.org/web/20120406064709/http://www.cisreg.ca/cgi-bin/tfe/articles.pl?tfid=156 |url-status=dead }}</ref>

Other studies in mice have found that TBR1 is a repressor or Fezf2. It has also been found to negatively regulate [[corticospinal tract]] formation.<ref name=Han/>

=== Zebrafish ===

Studies in the [[zebrafish]] ''Danio rerio'' show that TBR1 is highly conserved across species. TBR1 [[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.<ref name="Yonel-Tamura">{{cite journal | vauthors = Yonel-Tamura S, Tamura K, Tsukui T, Belmonte JC | title = Spatially and temporally-restricted expression of two T-box genes during zebrafish embryogenesis | journal = Mechanisms of Development | volume = 80 | issue = 2 | pages = 219–222 |date=February 1999 |  doi = 10.1016/S0925-4773(98)00219-6 | pmid = 10072792 | doi-access =  | s2cid = 980064 }}</ref>

=== 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.<ref name="Satoh">{{cite journal | vauthors = Satoh G, Takeuchi JK, Yasui K, Tagawa K, Saiga H, Zhang P, Satoh N | title = Amphi-Eomes/Tbr1: an amphioxus cognate of vertebrate Eomesodermin and T-Brain1 genes whose expression reveals evolutionarily distinct domain in amphioxus development | journal = The Journal of Experimental Zoology | volume = 294 | issue = 2 | pages = 136–145 | date = Aug 2002 | pmid = 12210114 | doi = 10.1002/jez.10149 | bibcode = 2002JEZ...294..136S }}</ref> However, lancelets lack a true brain and no TBR1 transcripts were found in the neural tissue of the lancelet.<ref name="Satoh"/> This suggests that the neuronal role of TBR1 evolved in vertebrates after the lancelet lineage had already diverged from that of vertebrates.<ref name=Bulfone/><ref name="Satoh"/>

== Gene regulation ==

TBR1 both positively and negatively regulates gene expression in postmitotic neurons.<ref name="Bedogni">{{cite journal | vauthors = Bedogni F, Hodge RD, Elsen GE, Nelson BR, Daza RA, Beyer RP, Bammler TK, Rubenstein JL, Hevner RF | title = Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 29 | pages = 13129–34 | date = Jul 2010 | pmid = 20615956 | pmc = 2919950 | doi = 10.1073/pnas.1002285107 | bibcode = 2010PNAS..10713129B | doi-access = free }}</ref>

=== 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.<ref name="Han">{{cite journal | vauthors = Han W, Kwan KY, Shim S, Lam MM, Shin Y, Xu X, Zhu Y, Li M, Sestan N | title = TBR1 directly represses Fezf2 to control the laminar origin and development of the corticospinal tract | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 7 | pages = 3041–6 | date = Feb 2011 | pmid = 21285371 | pmc = 3041103 | doi = 10.1073/pnas.1016723108 | bibcode = 2011PNAS..108.3041H | doi-access = free }}</ref> 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.<ref name=Han/>

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.<ref name=Bedogni/>

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 [[mental retardation]] and [[autism]].<ref name="Kalscheuer">{{cite journal | vauthors = Kalscheuer VM, FitzPatrick D, Tommerup N, Bugge M, Niebuhr E, Neumann LM, Tzschach A, Shoichet SA, Menzel C, Erdogan F, Arkesteijn G, Ropers HH, Ullmann R | title = Mutations in autism susceptibility candidate 2 (AUTS2) in patients with mental retardation | journal = Human Genetics | volume = 121 | issue = 3–4 | pages = 501–9 | date = May 2007 | pmid = 17211639 | doi = 10.1007/s00439-006-0284-0 | s2cid = 27503729 }}</ref><ref name="Sultana">{{cite journal | vauthors = Sultana R, Yu CE, Yu J, Munson J, Chen D, Hua W, Estes A, Cortes F, de la Barra F, Yu D, Haider ST, Trask BJ, Green ED, Raskind WH, Disteche CM, Wijsman E, Dawson G, Storm DR, Schellenberg GD, Villacres EC | title = Identification of a novel gene on chromosome 7q11.2 interrupted by a translocation breakpoint in a pair of autistic twins | journal = Genomics | volume = 80 | issue = 2 | pages = 129–34 | date = Aug 2002 | pmid = 12160723 | doi = 10.1006/geno.2002.6810 }}</ref> Auts2 is a target of the transcription factor, TBR1, in the neocortex.<ref name=Bedogni/> TBR1 is involved in both the binding and activation of the Auts2 gene.<ref name=Bedogni/>

=== Co-regulatory proteins ===

Tbr1 forms a complex with CASK and regulates gene expression in cortical development. Tbr1 binds to the [[guanylate kinase]] (GK) domain of CASK. It was determined that the [[C-terminal domain]] of Tbr1 in crucial and solely capable of this process.<ref name=Hseuh/> 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 ([[Interleukin-7 receptor|IL-7R]]) and OX-2 genes. NMDAR2b experienced the greatest change in activity.<ref name="Wang T">{{cite journal | vauthors = Wang TF, Ding CN, Wang GS, Luo SC, Lin YL, Ruan Y, Hevner R, Rubenstein JL, Hsueh YP | title = Identification of Tbr-1/CASK complex target genes in neurons | journal = Journal of Neurochemistry | volume = 91 | issue = 6 | pages = 1483–92 | date = Dec 2004 | pmid = 15584924 | doi = 10.1111/j.1471-4159.2004.02845.x | s2cid = 14671180 }}</ref>

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]].<ref name="pmid15066269">{{cite journal | vauthors = Wang GS, Hong CJ, Yen TY, Huang HY, Ou Y, Huang TN, Jung WG, Kuo TY, Sheng M, Wang TF, Hsueh YP | title = Transcriptional modification by a CASK-interacting nucleosome assembly protein | journal = Neuron | volume = 42 | issue = 1 | pages = 113–28 | date = Apr 2004 | pmid = 15066269 | doi = 10.1016/S0896-6273(04)00139-4 | doi-access = free }}</ref>

[[SOX5|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.<ref name=Bedogni/> It has been found that Sox5 interacts with Tbr1 to regulate Fezf2 transcription in layer VI cortical neurons.<ref name=Han/><ref name=Bedogni/>

=== 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.<ref name="Buttner">{{cite journal | vauthors = Büttner N, Johnsen SA, Kügler S, Vogel T | title = Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 15 | pages = 7042–7 | date = Apr 2010 | pmid = 20348416 | pmc = 2872432 | doi = 10.1073/pnas.0912041107 | bibcode = 2010PNAS..107.7042B | doi-access = free }}</ref> Mutants of Af9 experience increased dimethylation of H3K79 and increased TBR1 expression.<ref name=Buttner/>

== 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.<ref name="Pombero">{{cite journal | vauthors = Pombero A, Bueno C, Saglietti L, Rodenas M, Guimera J, Bulfone A, Martinez S | title = Pallial origin of basal forebrain cholinergic neurons in the nucleus basalis of Meynert and horizontal limb of the diagonal band nucleus | journal = Development | volume = 138 | issue = 19 | pages = 4315–4326 | date = Oct 2011 | pmid = 21865321 | doi = 10.1242/dev.069534 | doi-access = free | hdl = 10261/55015 | hdl-access = free }}</ref>

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.<ref name="Kristiansen">{{cite journal | vauthors = Kristiansen LV, Patel SA, Haroutunian V, Meador-Woodruff JH | title = Expression of the NR2B-NMDA receptor subunit and its Tbr-1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia | journal = Synapse | volume = 64 | issue = 7 | pages = 495–502 | date = Jul 2010 | pmid = 20175224 | doi = 10.1002/syn.20754 | s2cid = 26195679 }}</ref>

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.<ref>{{cite journal | vauthors = McCarthy DM, Zhang X, Darnell SB, Sangrey GR, Yanagawa Y, Sadri-Vakili G, Bhide PG | title = Cocaine alters BDNF expression and neuronal migration in the embryonic mouse forebrain | journal = The Journal of Neuroscience | volume = 31 | issue = 38 | pages = 13400–13411 | date = Sep 2011 | pmid = 21940433 | pmc = 3182852 | doi = 10.1523/JNEUROSCI.2944-11.2011 }}</ref>

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 (neuroanatomy)|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.<ref>{{cite journal | vauthors = Kishimoto N, Shimizu K, Sawamoto K | title = Neuronal regeneration in a zebrafish model of adult brain injury | journal = Disease Models & Mechanisms | volume = 5 | issue = 2 | pages = 200–9 | date = Mar 2012 | pmid = 22028327 | pmc = 3291641 | doi = 10.1242/dmm.007336 }}</ref>

Mutations of this gene have also been reported in the tissues of [[medulloblastoma]].<ref>{{cite journal | vauthors = Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, Cho YJ, Pugh TJ, Hovestadt V, Stütz AM, Rausch T, Warnatz HJ, Ryzhova M, Bender S, Sturm D, Pleier S, Cin H, Pfaff E, Sieber L, Wittmann A, Remke M, Witt H, Hutter S, Tzaridis T, Weischenfeldt J, Raeder B, Avci M, Amstislavskiy V, Zapatka M, Weber UD, Wang Q, Lasitschka B, Bartholomae CC, Schmidt M, von Kalle C, Ast V, Lawerenz C, Eils J, Kabbe R, Benes V, van Sluis P, Koster J, Volckmann R, Shih D, Betts MJ, Russell RB, Coco S, Tonini GP, Schüller U, Hans V, Graf N, Kim YJ, Monoranu C, Roggendorf W, Unterberg A, Herold-Mende C, Milde T, Kulozik AE, von Deimling A, Witt O, Maass E, Rössler J, Ebinger M, Schuhmann MU, Frühwald MC, Hasselblatt M, Jabado N, Rutkowski S, von Bueren AO, Williamson D, Clifford SC, McCabe MG, Collins VP, Wolf S, Wiemann S, Lehrach H, Brors B, Scheurlen W, Felsberg J, Reifenberger G, Northcott PA, Taylor MD, Meyerson M, Pomeroy SL, Yaspo ML, Korbel JO, Korshunov A, Eils R, Pfister SM, Lichter P | title = Dissecting the genomic complexity underlying medulloblastoma | journal = Nature | volume = 488 | issue = 7409 | pages = 100–5 | date = Aug 2012 | pmid = 22832583 | pmc = 3662966 | doi = 10.1038/nature11284 | bibcode = 2012Natur.488..100J }}</ref>

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 ==
* [[T-box]] family
* [[Eomesodermin|TBR2]]
* [[TBX21]]

== References ==
{{Reflist|colwidth=35em}}

== Further reading ==
{{refbegin|colwidth=35em}}
* {{cite journal | vauthors = Hsueh YP, Wang TF, Yang FC, Sheng M | title = Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2 | journal = Nature | volume = 404 | issue = 6775 | pages = 298–302 | date = Mar 2000 | pmid = 10749215 | doi = 10.1038/35005118 | bibcode = 2000Natur.404..298H | s2cid = 4415747 }}
* {{cite journal | vauthors = Stefanovska AM, Efremov GD, Dimovski AJ, Jasar D, Zografski G, Josifovski T, Panovski M, Jankova R, Spiroski M | title = 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 | journal = Cancer Research | volume = 61 | issue = 22 | pages = 8351–8352 | date = Nov 2001 | pmid = 11719470 }}
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{{Transcription factors|g4}}

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[[Category:Transcription factors]]
[[Category:Proteins]]
[[Category:Molecular neuroscience]]