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. The transcription factor is encoded by the TBX4 gene located on human chromosome 17. 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. Tbx4 has been shown to be expressed in the allantois, hindlimb, lung and proctodeum.
Function
Expression of Tbx4 is activated by a combined "caudal" Hox code, expressing a specified positional code that includes Pitx1 gene expression. The encoded protein plays a major role in limb development, specifically during limb bud initiation. For instance, in chickens Tbx4 specifies hindlimb status. 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. 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. Together with Tbx5, Tbx4 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.
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.
Mutations
Duplication of the 17q23.1–q23.2 region, which includes the TBX4 gene, has been reported to result in congenital clubfoot. TBX4 duplication within this region has been determined to be the gene that leads to this phenotype.
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. 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. 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). 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%).
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, 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.