TBX4

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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]

Contents

Function

Expression of Tbx4 is activated by a combined "caudal" Hox code, expressing a specified positional code that includes Pitx1 gene expression. [4] The encoded protein plays a major role in limb development, specifically during limb bud initiation. [5] For instance, in chickens Tbx4 specifies hindlimb status. [6] The activation of Tbx4 and other T-box proteins by Hox genes activates signaling cascades that involve the Wnt signaling pathway and FGF signals in limb buds. [5] Ultimately, Tbx4 leads to the development of apical ectodermal ridge (AER) and zone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb. [5] Together with Tbx5, Tbx4 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system. [7]

Role in non-human animals

In zebrafish, mutations in the nuclear localisation signal of Tbx4 results in the lack of pelvic fin structures, which are homologous to tetrapod hindlimbs. [8]

Mutations

Duplication of the 17q23.1–q23.2 region, which includes the TBX4 gene, has been reported to result in congenital clubfoot. [9] [10] TBX4 duplication within this region has been determined to be the gene that leads to this phenotype. [10]

Loss-of-function TBX4 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. [11] The loss of both parental copies of TBX4, resulting in a complete knockout, was reported by Bruno Reversade and colleagues to result in the total loss of hind limbs in human fetuses. [12] This fatal syndrome is known as posterior amelia with pelvic and pulmonary hypoplasia syndrome (PAPPAS).

Mutations in the TBX4 that cause small patella syndrome are also associated with childhood-onset pulmonary arterial hypertension (PAH). [13] 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%). [13]

Using targeted mutagenesis of Tbx4 in the mouse, various abnormalities were observed in the development of the allantois. Choirioallantoic fusion fails to occur in embryos with the homozygous null allele resulting in death 10.5 days post coitus, [14] embryos with the Tbx4-mutant gene were observed to have allantoises that were apoptotic, stunted, and displayed abnormal differentiation with endothelial cells resulting in the absence of vascular remodeling. [14]

Role

Tbx4 is a transcription factor and member of the T-box family, which have been shown to play important role in fetal development. [14] 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. [14] 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. [14] Along with Tbx4, Tbx5 is also expressed to help with development of limbs. [15] Tbx4 is expressed in the hindlimb, whereas Tbx5 is expressed in the forelimb, heart, and dorsal side of the retina. [16] Studies have shown that fibroblast growth factor (FGF) play a key role in limb initiation. [16] 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. [15] When these two molecules are expressed that stimulate the secretion of FGF-10, which will induce the ectoderm to produce FGF-8. [15] 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. [15] 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. [17] 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.

Related Research Articles

<span class="mw-page-title-main">Lateral plate mesoderm</span>

The lateral plate mesoderm is the mesoderm that is found at the periphery of the embryo. It is to the side of the paraxial mesoderm, and further to the axial mesoderm. The lateral plate mesoderm is separated from the paraxial mesoderm by a narrow region of intermediate mesoderm. The mesoderm is the middle layer of the three germ layers, between the outer ectoderm and inner endoderm.

<span class="mw-page-title-main">Myogenesis</span> Formation of muscular tissue, particularly during embryonic development

Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development.

<span class="mw-page-title-main">Apical ectodermal ridge</span>

The apical ectodermal ridge (AER) is a structure that forms from the ectodermal cells at the distal end of each limb bud and acts as a major signaling center to ensure proper development of a limb. After the limb bud induces AER formation, the AER and limb mesenchyme—including the zone of polarizing activity (ZPA)—continue to communicate with each other to direct further limb development.

<span class="mw-page-title-main">Limb development</span>

Limb development in vertebrates is an area of active research in both developmental and evolutionary biology, with much of the latter work focused on the transition from fin to limb.

The limb bud is a structure formed early in vertebrate limb development. As a result of interactions between the ectoderm and underlying mesoderm, formation occurs roughly around the fourth week of development. In the development of the human embryo the upper limb bud appears in the third week and the lower limb bud appears four days later.

<span class="mw-page-title-main">T-box</span> Genes that affect limb and heart development

T-box refers to a group of transcription factors involved in embryonic limb and heart development. Every T-box protein has a relatively large DNA-binding domain, generally comprising about a third of the entire protein that is both necessary and sufficient for sequence-specific DNA binding. All members of the T-box gene family bind to the "T-box", a DNA consensus sequence of TCACACCT.

<span class="mw-page-title-main">PITX2</span> Protein-coding gene in the species Homo sapiens

Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.

<span class="mw-page-title-main">FGF10</span> Protein-coding gene in humans

Fibroblast growth factor 10 is a protein that in humans is encoded by the FGF10 gene.

<i>TBX5</i> (gene) Protein-coding gene that affects limb development and heart and bone function

T-box transcription factor TBX5, is a protein that in humans is encoded by the TBX5 gene. Abnormalities in the TBX5 gene can result in altered limb development, Holt-Oram syndrome, Tetra-amelia syndrome, and cardiac and skeletal problems.

<span class="mw-page-title-main">Fibroblast growth factor 8</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 8(FGF-8) is a protein that in humans is encoded by the FGF8 gene.

<span class="mw-page-title-main">HOXD13</span> Protein

Homeobox protein Hox-D13 is a protein that in humans is encoded by the HOXD13 gene. This gene belongs to the homeobox family of genes. The homeobox genes encode a highly conserved family of transcription factors that play an important role in morphogenesis in all multicellular organisms.

<span class="mw-page-title-main">FGF4</span> Fibroblast growth factor gene

Fibroblast growth factor 4 is a protein that in humans is encoded by the FGF4 gene.

<span class="mw-page-title-main">TBX3</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX3 is a protein that in humans is encoded by the TBX3 gene.

<span class="mw-page-title-main">TBX2</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor 2 Tbx2 is a transcription factor that is encoded by the Tbx2 gene on chromosome 17q21-22 in humans. This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. Tbx2 and Tbx3 are the only T-box transcription factors that act as transcriptional repressors rather than transcriptional activators, and are closely related in terms of development and tumorigenesis. This gene plays a significant role in embryonic and fetal development through control of gene expression, and also has implications in various cancers. Tbx2 is associated with numerous signaling pathways, BMP, TGFβ, Wnt, and FGF, which allow for patterning and proliferation during organogenesis in fetal development.

<span class="mw-page-title-main">OSR1</span> Protein-coding gene in the species Homo sapiens

Protein odd-skipped-related 1 is a transcription factor that in humans is encoded by the OSR1 gene. The OSR1 and OSR2 transcription factors participate in the normal development of body parts such as the kidney.

<span class="mw-page-title-main">Zone of polarizing activity</span>

The zone of polarizing activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Eventually, the limb bud develops into bones, tendons, muscles and joints. Limb bud development relies not only on the ZPA, but also many different genes, signals, and a unique region of ectoderm called the apical ectodermal ridge (AER). Research by Saunders and Gasseling in 1948 identified the AER and its subsequent involvement in proximal distal outgrowth. Twenty years later, the same group did transplantation studies in chick limb bud and identified the ZPA. It wasn't until 1993 that Todt and Fallon showed that the AER and ZPA are dependent on each other.

<span class="mw-page-title-main">MESP2</span> Protein-coding gene in the species Homo sapiens

Mesoderm posterior protein 2 (MESP2), also known as class C basic helix-loop-helix protein 6 (bHLHc6), is a protein that in humans is encoded by the MESP2 gene.

The Cdx gene family, also called caudal genes, are a group of genes found in many animal genomes. Cdx genes contain a homeobox DNA sequence and code for proteins that act as transcription factors. The gene after which the gene family is named is the caudal or cad gene of the fruitfly Drosophila melanogaster. The human genome has three Cdx genes, called CDX1, CDX2 and CDX4. The zebrafish has no cdx2 gene, but two copies of cdx1 and one copy of cdx4. The Cdx gene in the nematode Caenorhabditis elegans is called pal-1.

<span class="mw-page-title-main">TBX15</span> Human protein and coding gene

T-box transcription factor TBX15 is protein that is encoded in humans by the Tbx15 gene, mapped to Chromosome 3 in mice and Chromosome 1 in humans. Tbx15 is a transcription factor that plays a key role in embryonic development. Like other members of the T-box subfamily, Tbx15 is expressed in the notochord and primitive streak, where it assists with the formation and differentiation of the mesoderm. It is steadily downregulated after segmentation of the paraxial mesoderm.

<span class="mw-page-title-main">Ischiopatellar dysplasia</span> Medical condition

Ischiopatellar dysplasia is a rare autosomal dominant disorder characterized by a hypoplasia of the patellae as well as other bone anomalies, especially concerning the pelvis and feet. It is also known as small patella syndrome, with earlier synonyms being Scott-Taor syndrome, Coxo-podo-patellar syndrome, Patella aplasia, coxa vara, tarsal synostosis, Congenital coxa vara, patella aplasia and tarsal synostosis ischiocoxopodopatellar syndrome.

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.
  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. PMC   3180884 . PMID   21932311.
  4. ↑ Minguillon, Carolina; Buono, Jo Del; Logan, Malcolm 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.
  5. 1 2 3 Tickle C (2015). "How the embryo makes a limb: determination, polarity and identity". J. Anat. 227 (4): 418–30. doi:10.1111/joa.12361. PMC   4580101 . PMID   26249743.
  6. ↑ Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC (1999). "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity". Nature. 398 (6730): 814–8. Bibcode:1999Natur.398..814R. doi:10.1038/19769. PMID   10235264. S2CID   4330287.
  7. ↑ Hasson, Peleg; DeLaurier, April; Bennett, Michael; Grigorieva, Elena; Naice, L.A.; Papaioannou, Virginia E.; Mohun, Timothy J.; Logan, Malcolm 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.
  8. ↑ Don, Emily K.; de Jong-Curtain, Tanya A.; Doggett, Karen; Hall, Thomas E.; Heng, Benjamin; Badrock, Andrew P.; Winnick, Claire; Nicholson, Garth A.; Guillemin, Gilles J.; Currie, Peter D.; Hesselson, Daniel; Heath, Joan K.; Cole, Nicholas J. (15 March 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. Archived from the original on 28 May 2023. Retrieved 28 May 2023.
  9. ↑ 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. PMC   2896772 . PMID   20598276.
  10. 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. S2CID   205318198.
  11. ↑ 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. PMC   1182087 . PMID   15106123.
  12. ↑ Kariminejad, Ariana; Szenker-Ravi, Emmanuelle; Lekszas, Caroline; Tajsharghi, Homa; Moslemi, Ali-Reza; Naert, Thomas; Tran, Hong Thi; Ahangari, Fatemeh; Rajaei, Minoo; Nasseri, Mojila; Haaf, Thomas (2019-12-05). "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. ISSN   1537-6605. PMC   6904794 . PMID   31761294.
  13. 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. PMC   3717587 . PMID   23592887.
  14. 1 2 3 4 5 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 . PMID   12736212.
  15. 1 2 3 4 Carlson: Human Embryology and Developmental Biology, 4th Edition. Copyright 2009 by Mosby. 184-205.
  16. 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 . PMID   12736216.
  17. ↑ 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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