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