# TBX4

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{{Short description|Protein-coding gene in humans}}
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{{Infobox gene}}

'''T-box transcription factor Tbx4''' is a [transcription factor](/source/transcription_factor) that belongs to [T-box](/source/T-box) gene family that is involved in the regulation of [embryonic developmental processes](/source/Embryogenesis).<ref name="NCBI">{{cite web | title = TBX4 T-box 4 [ Homo sapiens (human) ] | url = https://www.ncbi.nlm.nih.gov/gene/9496 | website = NCBI | access-date = 15 April 2015 }}</ref><ref name="Yi_2000">{{cite journal | vauthors = Yi CH, Russ A, Brook JD | title = Virtual cloning and physical mapping of a human T-box gene, TBX4 | journal = Genomics | volume = 67 | issue = 1 | pages = 92–95 | date = July 2000 | pmid = 10945475 | doi = 10.1006/geno.2000.6222 }}</ref> The transcription factor is encoded by the TBX4 gene located on [human chromosome 17](/source/Chromosome_17_(human)).<ref name="Yi_2000" /> Tbx4 is known mostly for its role in the development of the [hindlimb](/source/hindlimb), but it also plays a critical role in the formation of the [umbilicus](/source/Umbilical_cord).<ref name="Naiche_2011">{{cite journal | vauthors = Naiche LA, Arora R, Kania A, Lewandoski M, Papaioannou VE | title = Identity and fate of Tbx4-expressing cells reveal developmental cell fate decisions in the allantois, limb, and external genitalia | journal = Developmental Dynamics | volume = 240 | issue = 10 | pages = 2290–2300 | date = October 2011 | pmid = 21932311 | pmc = 3180884 | doi = 10.1002/dvdy.22731 }}</ref> Tbx4 has been shown to be expressed in the [allantois](/source/allantois), hindlimb, [lung](/source/lung) and [proctodeum](/source/proctodeum).<ref name="Naiche_2011" />

== Tissue distribution ==

Tbx4 is expressed in a wide variety of tissues during [organogenesis](/source/organogenesis), including the hindlimb, proctodeum, mandibular [mesenchyme](/source/mesenchyme), lung mesenchyme, [atrium of the heart](/source/Atrium_(heart)) and the body wall.<ref name="Naiche_2003"/> Tbx4 is specifically expressed in the visceral [mesoderm](/source/mesoderm) of the lung [primordium](/source/primordium) and governs multiple processes during [respiratory tract](/source/respiratory_tract) development such as initial endodermal bud development, respiratory [endoderm](/source/endoderm) formation, and septation of the respiratory tract and esophagus.<ref name="Naiche_2003"/> Along with Tbx4, Tbx5 is also expressed to help with development of limbs.<ref name="Carlson_2009">{{cite book | vauthors = Carlson BM | title = Human Embryology and Developmental Biology | edition = 4th | date = 2009 | publisher = Mosby | pages = 184–205 }}</ref> Tbx4 is expressed in the hindlimb, whereas Tbx5 is expressed in the forelimb, heart, and dorsal side of the [retina](/source/retina).<ref name="Takeuchi_2003">{{cite journal | vauthors = Takeuchi JK, Koshiba-Takeuchi K, Suzuki T, Kamimura M, Ogura K, Ogura T | title = Tbx5 and Tbx4 trigger limb initiation through activation of the Wnt/Fgf signaling cascade | journal = Development | volume = 130 | issue = 12 | pages = 2729–2739 | date = June 2003 | pmid = 12736216 | doi = 10.1242/dev.00474 | doi-access = free }}</ref>

== Function ==
Tbx4 is a transcription factor and a member of the T-box family, which play important roles in [fetal development](/source/Prenatal_development).<ref name="Naiche_2003">{{cite journal | vauthors = Naiche LA, Papaioannou VE | title = Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois | journal = Development | volume = 130 | issue = 12 | pages = 2681–2693 | date = June 2003 | pmid = 12736212 | doi = 10.1242/dev.00504 | doi-access = free }}</ref>  

In the developing embryo, [Fibroblast growth factor](/source/Fibroblast_growth_factor) (FGF) signaling plays a key role in limb initiation.<ref name="Takeuchi_2003"/> A gradient of [retinoic acid](/source/retinoic_acid) establishes combinatorial patterns of [Hox](/source/Hox_genes) expression along the body axis, leading regions of the [paraxial mesoderm](/source/paraxial_mesoderm) to signal the [lateral mesoderm](/source/lateral_mesoderm) and induce expression of Tbx4 and Tbx5.<ref name="Carlson_2009" /> These factors stimulate the secretion of [FGF-10](/source/FGF10), which in turn induces the overlying ectoderm to produce [FGF-8](/source/FGF8).<ref name="Carlson_2009" /> Together, FGF-8 and FGF-10 promote limb outgrowth.  

Tbx4 expression is regulated by a "caudal" [Hox code](/source/Hox_genes) that includes activation of the [Pitx1](/source/Pitx1) gene, conferring positional identity.<ref name="Minguillon_2005">{{cite journal | vauthors = Minguillon C, Del Buono J, Logan MP | title = Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth | journal = Developmental Cell | volume = 8 | issue = 1 | pages = 75–84 | date = January 2005 | pmid = 15621531 | doi = 10.1016/j.devcel.2004.11.013 | doi-access = free }}</ref> The protein product is essential for [limb development](/source/limb_development), particularly during [limb bud](/source/limb_bud) initiation.<ref name="Tickle_2015">{{cite journal | vauthors = Tickle C | title = How the embryo makes a limb: determination, polarity and identity | journal = Journal of Anatomy | volume = 227 | issue = 4 | pages = 418–430 | date = October 2015 | pmid = 26249743 | pmc = 4580101 | doi = 10.1111/joa.12361 }}</ref> In chickens, for example, Tbx4 specifies hindlimb identity.<ref name="RodriguezEsteban_1999">{{cite journal | vauthors = Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC | title = The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity | journal = Nature | volume = 398 | issue = 6730 | pages = 814–818 | date = April 1999 | pmid = 10235264 | doi = 10.1038/19769 | s2cid = 4330287 | bibcode = 1999Natur.398..814R }}</ref>  Activation of Tbx4 and other T-box proteins by Hox genes initiates [signaling cascade](/source/signaling_cascade)s involving the [Wnt signaling pathway](/source/Wnt_signaling_pathway) and FGF signals in limb buds.<ref name="Tickle_2015" /> These cascades establish the [apical ectodermal ridge (AER)](/source/Apical_ectodermal_ridge) and [zone of polarizing activity (ZPA)](/source/Zone_of_polarizing_activity)—two key signaling centers that direct the orientation and growth of the developing limb.<ref name="Tickle_2015" />  

In addition to its role in outgrowth, Tbx4 cooperates with [Tbx5](/source/Tbx5) to pattern the [soft tissue](/source/soft_tissue)s of the [musculoskeletal system](/source/musculoskeletal_system), including muscles and tendons.<ref name="Hasson_2010">{{cite journal | vauthors = Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP | title = Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning | journal = Developmental Cell | volume = 18 | issue = 1 | pages = 148–156 | date = January 2010 | pmid = 20152185 | pmc = 3034643 | doi = 10.1016/j.devcel.2009.11.013 }}</ref> In [zebrafish](/source/zebrafish), mutations in the nuclear localisation signal of Tbx4 result in the absence of pelvic fin structures, which are homologous to tetrapod hindlimbs.<ref>{{cite journal | vauthors = Don EK, de Jong-Curtain TA, Doggett K, Hall TE, Heng B, Badrock AP, Winnick C, Nicholson GA, Guillemin GJ, Currie PD, Hesselson D, Heath JK, Cole NJ | title = Genetic basis of hindlimb loss in a naturally occurring vertebrate model | journal = Biology Open | volume = 5 | issue = 3 | pages = 359–366 | date = February 2016 | pmid = 26892237 | pmc = 4810746 | doi = 10.1242/bio.016295 | publisher = [Biology Open](/source/Biology_Open) | author9-link = Gilles J. Guillemin }}</ref>

== Clinical significance ==

Mutations in TBX4 and related genes are associated with a range of developmental disorders affecting the limbs, pelvis, lungs, and vascular system. One of the most severe conditions is [tetra-amelia syndrome](/source/Tetra-amelia_syndrome), characterized by the absence of all four limbs and anomalies of the [skull](/source/skull), face, eyes, urogenital system, heart, lungs, and central nervous system.<ref>{{cite book | vauthors = Niemann S | chapter = Tetra-Amelia Syndrome | veditors = Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A | title = GeneReviews | year = 2007 | publisher = University of Washington, Seattle | pmid = 20301453 | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK1276/ }}</ref> In a study by Naiche et al., a [knockout mouse](/source/knockout_mouse) lacking Tbx4 expression failed to develop limbs, demonstrating the gene’s essential role in limb formation.<ref name="Naiche_2003"/>  

Duplication of the 17q23.1–q23.2 region, which includes TBX4, has been reported in cases of congenital [clubfoot](/source/clubfoot).<ref>{{cite journal | vauthors = Alvarado DM, Aferol H, McCall K, Huang JB, Techy M, Buchan J, Cady J, Gonzales PR, Dobbs MB, Gurnett CA | title = Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4 | journal = American Journal of Human Genetics | volume = 87 | issue = 1 | pages = 154–160 | date = July 2010 | pmid = 20598276 | pmc = 2896772 | doi = 10.1016/j.ajhg.2010.06.010 | author10-link = Christina Gurnett }}</ref><ref name="Peterson_2014">{{cite journal | vauthors = Peterson JF, Ghaloul-Gonzalez L, Madan-Khetarpal S, Hartman J, Surti U, Rajkovic A, Yatsenko SA | title = Familial microduplication of 17q23.1–q23.2 involving TBX4 is associated with congenital clubfoot and reduced penetrance in females | journal = American Journal of Medical Genetics. Part A | volume = 164A | issue = 2 | pages = 364–369 | date = February 2014 | pmid = 24592505 | doi = 10.1002/ajmg.a.36238 | s2cid = 205318198 }}</ref> TBX4 duplication within this locus has been identified as the causative factor for this [phenotype](/source/phenotype).<ref name="Peterson_2014" />  Disruption of Tbx4, Tbx5, or the downstream [FGF-8/FGF-10](/source/Fibroblast_growth_factor) signaling pathway can also result in severe limb reduction defects, including the complete absence of one or more limbs.<ref name="Carlson_2009" />  

Loss-of-function mutations in TBX4 cause the [autosomal dominant](/source/autosomal_dominant) disorder [small patella syndrome](/source/Ischiopatellar_dysplasia) (also called Scott-Taor syndrome), characterized by patellar [aplasia](/source/aplasia) and malformations of the pelvis and feet.<ref name="Bongers_2004">{{cite journal | vauthors = Bongers EM, Duijf PH, van Beersum SE, Schoots J, Van Kampen A, Burckhardt A, Hamel BC, Losan F, Hoefsloot LH, Yntema HG, Knoers NV, van Bokhoven H | title = Mutations in the human TBX4 gene cause small patella syndrome | journal = American Journal of Human Genetics | volume = 74 | issue = 6 | pages = 1239–1248 | date = June 2004 | pmid = 15106123 | pmc = 1182087 | doi = 10.1086/421331 }}</ref> Homozygous null mutations, in which both parental copies of TBX4 are lost, were reported by [Bruno Reversade](/source/Bruno_Reversade) and colleagues to result in the complete absence of hind limbs in human fetuses.<ref>{{cite journal | vauthors = Kariminejad A, Szenker-Ravi E, Lekszas C, Tajsharghi H, Moslemi AR, Naert T, Tran HT, Ahangari F, Rajaei M, Nasseri M, Haaf T, Azad A, Superti-Furga A, Maroofian R, Ghaderi-Sohi S, Najmabadi H, Abbaszadegan MR, Vleminckx K, Nikuei P, Reversade B | title = Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia | journal = American Journal of Human Genetics | volume = 105 | issue = 6 | pages = 1294–1301 | date = December 2019 | pmid = 31761294 | pmc = 6904794 | doi = 10.1016/j.ajhg.2019.10.013 }}</ref> This lethal condition is known as posterior amelia with pelvic and pulmonary hypoplasia syndrome (PAPPAS).  

Mutations in TBX4 associated with small patella syndrome have also been linked to childhood-onset [pulmonary arterial hypertension](/source/pulmonary_arterial_hypertension) (PAH).<ref name="Kerstjens-Frederikse_2013">{{cite journal | vauthors = Kerstjens-Frederikse WS, Bongers EM, Roofthooft MT, Leter EM, Douwes JM, Van Dijk A, Vonk-Noordegraaf A, Dijk-Bos KK, Hoefsloot LH, Hoendermis ES, Gille JJ, Sikkema-Raddatz B, Hofstra RM, Berger RM | title = TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension | journal = Journal of Medical Genetics | volume = 50 | issue = 8 | pages = 500–506 | date = August 2013 | pmid = 23592887 | pmc = 3717587 | doi = 10.1136/jmedgenet-2012-101152 }}</ref> [Deletion](/source/Deletion_(genetics)) of 17q23.2 (encompassing TBX4) or [point mutation](/source/point_mutation)s in TBX4 are found in ~30% of childhood-onset PAH cases, but occur far less frequently in adults (~2%).<ref name="Kerstjens-Frederikse_2013"" />  

In mouse models, [site-directed mutagenesis](/source/site-directed_mutagenesis) of Tbx4 has revealed additional developmental roles. Homozygous [null allele](/source/null_allele)s disrupt development of the [allantois](/source/allantois), preventing [chorioallantoic](/source/Chorioallantoic_membrane) fusion and resulting in embryonic death at ~10.5 days post coitus.<ref name="Naiche_2003"/> Mutant embryos display apoptotic and stunted allantoises with abnormal endothelial differentiation, leading to failure of [vascular remodeling](/source/Vascular_remodelling_in_the_embryo).<ref name="Naiche_2003"/>

== References ==
{{Reflist}}

Category:Transcription factors

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Adapted from the Wikipedia article [TBX4](https://en.wikipedia.org/wiki/TBX4) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/TBX4?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.