TBX4

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.[1][2] The transcription factor is encoded by the TBX4 gene located on human chromosome 17.[2] 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.[3] Tbx4 has been shown to be expressed in the allantois, hindlimb, lung and proctodeum.[3]

Function

Expression of Tbx4 is required for hindlimb outgrowth and is activated by a combined "caudal" Hox code, expressing a specified positional code that includes Pitx1.[4] Together with Tbx5, Tbx4 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.[5]

Mutations

Duplication of the 17q23.1–q23.2 region, which includes the Tbx4 gene, has been reported to result in congenital clubfoot.[6][7] Tbx4 duplication within this region has been determined to be the gene that leads to this phenotype.[7]

TBX4 gene mutations lead to an autosomal-dominant disorder called small patella syndrome, also known as Scott-Taor syndrome, which is characterized by patellar aplasia and abnormalities of the pelvis and feet.[8]

Mutations in the TBX4 that cause small patella syndrome are also associated with childhood-onset pulmonary arterial hypertension (PAH).[9] Deletion of 17q23.2 (which includes the TBX4 gene) or a point mutation in the TBX4 gene is reported in 30% of patients with childhood-onset PAH, whereas TBX4 gene mutations are associated with low frequency in adult-onset PAH patients (2%).[9]

Role

Tbx4 is a transcription factor and member of the T-box family, which have been shown to play important role in fetal development.[10] 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.[10] Along with Tbx4, Tbx5 is also expressed to help with development of limbs.[11] Tbx4 is expressed in the hindlimb, whereas Tbx5 is expressed in the forelimb, heart, and dorsal side of the retina.[12] Studies have shown that fibroblast growth factor (FGF) play a key role in limb initiation.[12] In a developing embryo a gradient of retinoic acid aids in the combinatorial patterns of Hox gene expression along the body axis, which causes regions of the paraxial mesoderm to emit a signal to the lateral mesoderm that causes the expression of Tbx4 and Tbx5.[11] When these two molecules are expressed that stimulate the secretion of FGF-10, which will induce the ectoderm to produce FGF-8.[11] FGF-8 and FGF-10 together promote limb development. Mutations or teratogens that interfere with Tbx4/Tbx5 or FGF-8/FGF-10 has the ability to cause a child to be born without one or more limbs.[11] A common syndrome seen with a mutation these genes is Tetra-Amelia syndrome which is characterized by the absence of all four limbs and anomalies involving the cranium and the face; eyes; urogenital system; heart; lungs and central nervous system.[13] In a study done by Naiche et al. they generated a knockout mouse in which it lacked the expression on Tbx4 this mouse resulted in a phenotype of no limb formation.

References

  1. ↑ "TBX4 T-box 4 [ Homo sapiens (human) ]". NCBI. Retrieved 15 April 2015.
  2. 1 2 Cheong-Ho, Yi (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. Retrieved 15 April 2015.
  3. 1 2 Naiche, L.A.; Arora, Ripla; Kania, Artur; Lewandoski, Mark; Papaioannou, Virginia E. (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. PMID 21932311.
  4. ↑ Minguillon, Carolina; Buono, Jo Del; Logan, Malcom P/ (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. Retrieved 15 April 2015.
  5. ↑ Hasson, Peleg; DeLaurier, April; Bennett, Michael; Grigorieva, Elena; Naice, L.A.; Papaioannou, Virginia E.; Mohun, Timothy J.; Logan, Malcom P.O. (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.
  6. ↑ Alvarado, David M.; Aferol, Hyuliya; McCall, Kevin; Huang, Jason B.; Techy, Matthew; Buchan, Jillian; Cady, Janet; Gonzales, Patrick R.; Dobbs, Matthew B.; Gurnett, Christina A. (July 2010). "Familial Isolated Clubfoot Is Associated with Recurrent Chromosome 17q23.1q23.2 Microduplications Containing TBX4". The American Journal of Human Genetics 87 (1): 154–160. doi:10.1016/j.ajhg.2010.06.010. PMID 20598276.
  7. 1 2 Peterson, Jess F.; Ghaloul-Gonzalez, Lina; Madan-Khetarpal, Suneeta; Hartman, Jessica; Surti, Urvashi; Rajkovic, Aleksandar; Yatsenko, Svetlana A. (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 164 (2): 364–369. doi:10.1002/ajmg.a.36238. PMID 24592505. Retrieved 15 April 2015.
  8. ↑ Bongers, Ernie M.H.F.; Duijf, Pascal H.G.; van Beersum, Sylvia E.M.; Schoots, Jeroen; van Kampen, Albert; Burckhardt, Andreas; Hamel, Ben C.J.; Lošan, František; Hoefsloot, Lies H.; Yntema, Helger G.; Knoers, Nine V.A.M.; van Bokhoven, Hans (2004). "Mutations in the Human TBX4 Gene Cause Small Patella Syndrome". The American Journal of Human Genetics 74 (6): 1239–1248. doi:10.1086/421331. PMID 15106123. Retrieved 15 April 2015.
  9. 1 2 Kerstjens-Frederikse, Wilhelmina S; Bongers, Ernie M H F; Roofthooft, Marcus T R; Leter, Edward M; Douwes, J Menno; Van Dijk, Arie; Vonk-Noordegraaf, Anton; Dijk-Box, Krista; Hoefsloot, Lies H; Hoendermis, Elke S; Gille, Johan J P; Sikkema-Raddatz, Birgit; Hofstra, Robert M W; Berger, Riolf M F (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. PMID 23592887. Retrieved 15 April 2015.
  10. 1 2 Naiche, L.A.; Papaiannou, V.E. (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.
  11. 1 2 3 4 Carlson: Human Embryology and Developmental Biology, 4th Edition. Copyright 2009 by Mosby. 184-205.
  12. 1 2 Takeuchi, J.K.; K-Takeuchi, K.; Suzuki, T.; Kamimura, M.; Ogura, K.; Ogura, T. (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.
  13. ↑ Pagon, R.A.; Adam, M.P.; Ardinger, H.H.; Wallace, S.E.; Amemiya, A.; Bean, L.J.H.; Bird, T.D.; Dolan, C.R.; Fong, C.T.; Smith, R.J.H.; Stephens, K. (2007). "Tetra-Amelia Syndrome". GeneReviews. PMID 20301453.
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