TBX4

Last updated

TBX4
Identifiers
Aliases TBX4 , SPS, ICPPS, T-box 4, T-box transcription factor 4, PAPPAS
External IDs OMIM: 601719; MGI: 102556; HomoloGene: 7968; GeneCards: TBX4; OMA:TBX4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_018488
NM_001321120

NM_011536
NM_172798

RefSeq (protein)

NP_001308049
NP_060958

NP_035666
NP_766386

Location (UCSC) Chr 17: 61.45 – 61.49 Mb Chr 11: 85.78 – 85.81 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. [5] [6] The transcription factor is encoded by the TBX4 gene located on human chromosome 17. [6] 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. [7] Tbx4 has been shown to be expressed in the allantois, hindlimb, lung and proctodeum. [7]

Contents

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. [8] 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. [8] Along with Tbx4, Tbx5 is also expressed to help with development of limbs. [9] Tbx4 is expressed in the hindlimb, whereas Tbx5 is expressed in the forelimb, heart, and dorsal side of the retina. [10]

Function

Tbx4 is a transcription factor and a member of the T-box family, which play important roles in fetal development. [8]

In the developing embryo, Fibroblast growth factor (FGF) signaling plays a key role in limb initiation. [10] 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. [9] These factors stimulate the secretion of FGF-10, which in turn induces the overlying ectoderm to produce FGF-8. [9] 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. [11] The protein product is essential for limb development, particularly during limb bud initiation. [12] In chickens, for example, Tbx4 specifies hindlimb identity. [13] 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. [12] 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. [12]

In addition to its role in outgrowth, Tbx4 cooperates with Tbx5 to pattern the soft tissues of the musculoskeletal system, including muscles and tendons. [14] In zebrafish, mutations in the nuclear localisation signal of Tbx4 result in the absence of pelvic fin structures, which are homologous to tetrapod hindlimbs. [15]

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. [16] 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. [8]

Duplication of the 17q23.1–q23.2 region, which includes TBX4, has been reported in cases of congenital clubfoot. [17] [18] TBX4 duplication within this locus has been identified as the causative factor for this phenotype. [18] 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. [9]

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. [19] 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. [20] 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). [21] 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%). [21]

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. [8] Mutant embryos display apoptotic and stunted allantoises with abnormal endothelial differentiation, leading to failure of vascular remodeling. [8]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000121075 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000094 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. "TBX4 T-box 4 [ Homo sapiens (human) ]". NCBI. Retrieved 15 April 2015.
  6. 1 2 Yi CH, Russ A, Brook JD (July 2000). "Virtual cloning and physical mapping of a human T-box gene, TBX4". Genomics. 67 (1): 92–95. doi:10.1006/geno.2000.6222. PMID   10945475.
  7. 1 2 Naiche LA, Arora R, Kania A, Lewandoski M, Papaioannou VE (October 2011). "Identity and fate of Tbx4-expressing cells reveal developmental cell fate decisions in the allantois, limb, and external genitalia". Developmental Dynamics. 240 (10): 2290–2300. doi:10.1002/dvdy.22731. PMC   3180884 . PMID   21932311.
  8. 1 2 3 4 5 6 Naiche LA, Papaioannou VE (June 2003). "Loss of Tbx4 blocks hindlimb development and affects vascularization and fusion of the allantois". Development. 130 (12): 2681–2693. doi: 10.1242/dev.00504 . PMID   12736212.
  9. 1 2 3 4 Carlson BM (2009). Human Embryology and Developmental Biology (4th ed.). Mosby. pp. 184–205.
  10. 1 2 Takeuchi JK, Koshiba-Takeuchi K, Suzuki T, Kamimura M, Ogura K, Ogura T (June 2003). "Tbx5 and Tbx4 trigger limb initiation through activation of the Wnt/Fgf signaling cascade". Development. 130 (12): 2729–2739. doi: 10.1242/dev.00474 . PMID   12736216.
  11. Minguillon C, Del Buono J, Logan MP (January 2005). "Tbx5 and Tbx4 are not sufficient to determine limb-specific morphologies but have common roles in initiating limb outgrowth". Developmental Cell. 8 (1): 75–84. doi: 10.1016/j.devcel.2004.11.013 . PMID   15621531.
  12. 1 2 3 Tickle C (October 2015). "How the embryo makes a limb: determination, polarity and identity". Journal of Anatomy. 227 (4): 418–430. doi:10.1111/joa.12361. PMC   4580101 . PMID   26249743.
  13. Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC (April 1999). "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity". Nature. 398 (6730): 814–818. Bibcode:1999Natur.398..814R. doi:10.1038/19769. PMID   10235264. S2CID   4330287.
  14. Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, et al. (January 2010). "Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning". Developmental Cell. 18 (1): 148–156. doi:10.1016/j.devcel.2009.11.013. PMC   3034643 . PMID   20152185.
  15. Don EK, de Jong-Curtain TA, Doggett K, Hall TE, Heng B, Badrock AP, et al. (February 2016). "Genetic basis of hindlimb loss in a naturally occurring vertebrate model". Biology Open. 5 (3). Biology Open: 359–366. doi:10.1242/bio.016295. PMC   4810746 . PMID   26892237.
  16. Niemann S (2007). "Tetra-Amelia Syndrome". In Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A (eds.). GeneReviews. University of Washington, Seattle. PMID   20301453.
  17. Alvarado DM, Aferol H, McCall K, Huang JB, Techy M, Buchan J, et al. (July 2010). "Familial isolated clubfoot is associated with recurrent chromosome 17q23.1q23.2 microduplications containing TBX4". American Journal of Human Genetics. 87 (1): 154–160. doi:10.1016/j.ajhg.2010.06.010. PMC   2896772 . PMID   20598276.
  18. 1 2 Peterson JF, Ghaloul-Gonzalez L, Madan-Khetarpal S, Hartman J, Surti U, Rajkovic A, et al. (February 2014). "Familial microduplication of 17q23.1–q23.2 involving TBX4 is associated with congenital clubfoot and reduced penetrance in females". American Journal of Medical Genetics. Part A. 164A (2): 364–369. doi:10.1002/ajmg.a.36238. PMID   24592505. S2CID   205318198.
  19. Bongers EM, Duijf PH, van Beersum SE, Schoots J, Van Kampen A, Burckhardt A, et al. (June 2004). "Mutations in the human TBX4 gene cause small patella syndrome". American Journal of Human Genetics. 74 (6): 1239–1248. doi:10.1086/421331. PMC   1182087 . PMID   15106123.
  20. Kariminejad A, Szenker-Ravi E, Lekszas C, Tajsharghi H, Moslemi AR, Naert T, et al. (December 2019). "Homozygous Null TBX4 Mutations Lead to Posterior Amelia with Pelvic and Pulmonary Hypoplasia". American Journal of Human Genetics. 105 (6): 1294–1301. doi:10.1016/j.ajhg.2019.10.013. PMC   6904794 . PMID   31761294.
  21. 1 2 Kerstjens-Frederikse WS, Bongers EM, Roofthooft MT, Leter EM, Douwes JM, Van Dijk A, et al. (August 2013). "TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension". Journal of Medical Genetics. 50 (8): 500–506. doi:10.1136/jmedgenet-2012-101152. PMC   3717587 . PMID   23592887.