TBX4

{{Short description|Protein-coding gene in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}}

'''T-box transcription factor Tbx4''' is a transcription factor that belongs to T-box gene family that is involved in the regulation of embryonic developmental processes.<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.<ref name="Yi_2000" /> Tbx4 is known mostly for its role in the development of the hindlimb, but it also plays a critical role in the formation of the umbilicus.<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, hindlimb, lung and proctodeum.<ref name="Naiche_2011" />

== Tissue distribution ==

Tbx4 is expressed in a wide variety of tissues during organogenesis, including the hindlimb, proctodeum, mandibular mesenchyme, lung mesenchyme, atrium of the heart and the body wall.<ref name="Naiche_2003"/> Tbx4 is specifically expressed in the visceral mesoderm of the lung primordium and governs multiple processes during respiratory tract development such as initial endodermal bud development, respiratory 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.<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.<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 (FGF) signaling plays a key role in limb initiation.<ref name="Takeuchi_2003"/> A gradient of retinoic acid establishes combinatorial patterns of Hox expression along the body axis, leading regions of the paraxial mesoderm to signal the lateral mesoderm and induce expression of Tbx4 and Tbx5.<ref name="Carlson_2009" /> These factors stimulate the secretion of FGF-10, which in turn induces the overlying ectoderm to produce FGF-8.<ref name="Carlson_2009" /> Together, FGF-8 and FGF-10 promote limb outgrowth.

Tbx4 expression is regulated by a "caudal" Hox code that includes activation of the 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, particularly during 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 cascades involving the Wnt signaling pathway and FGF signals in limb buds.<ref name="Tickle_2015" /> These cascades establish the apical ectodermal ridge (AER) and zone of polarizing activity (ZPA)—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 to pattern the soft tissues of the 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, 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 | 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, characterized by the absence of all four limbs and anomalies of the 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 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.<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.<ref name="Peterson_2014" /> Disruption of Tbx4, Tbx5, or the downstream FGF-8/FGF-10 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 disorder small patella syndrome (also called Scott-Taor syndrome), characterized by patellar 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 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 (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 of 17q23.2 (encompassing TBX4) or point mutations 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 of Tbx4 has revealed additional developmental roles. Homozygous null alleles disrupt development of the allantois, preventing chorioallantoic 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.<ref name="Naiche_2003"/>

== References == {{Reflist}}

Category:Transcription factors