TBX15

The most notable effect of Tbx15 is its role in skeletal development. Tbx15 null mutant mice display prominent issues with skeletal development as prehypertrophic chondrocytes and mesenchymal precursor cells fail to proliferate as expected. Cartilaginous templates are reduced, with delays in ossification later in fetal development. This results in reduced bone size as well as alterations to the bone shape. In the forelimb, the central region of the scapular blade never forms, resulting in a hole through the scapula itself.[8]

Tbx15 appears to play a synergistic role with Gli3 and Alx4 in the formation of the skeletal features of the shoulder girdle, with more pronounced malformations seen in cases where multiple mutations arise.[11] Most likely, this reflects Tbx15’s role in positional guidance of progenitor cells. Tbx18 is closely related to Tbx15, and it is generally co-expressed with Tbx15 in the core of the limb bud. However, Tbx18 null mice express no limb defects unless Pax3 is deactivated as well.[12]

Tbx15 mutations can present in mice as irregular skin or fur color. This is due to a regulatory role in the correct expression of Agouti.When deactivated, Agouti expression is displaced dorsally.[13] This reflects Tbx15’s role in determining the limb dorsoventral boundary during early fetal development rather than any direct influence on the ectoderm. It helps to regulate the differentiation of the dorsolateral mesenchyme, which in turn is used to later determine the position and identity of the dorsal dermis.

In-utero methylation of Tbx15 plays a role in overall fetal growth, with hypomethylation having a demonstrable effect on placental functioning. Vascular intrauterine growth restriction follows, and it may have a correlation with increased rates of preeclampsia.[14] Tbx15 also down-regulates the mass of mitochondria and the rate of basal mitochondrial expression, with both decreasing significantly if the gene is overexpressed.[15]

Tbx15 plays a role in adipocyte differentiation, with 260-fold higher expression in subcutaneous preadipocytes than epididymal (visceral) preadipocytes. Overexpression of Tbz15 can lead to impaired differentiation and abnormally low levels of triglycerides.[15] Crucially, Tbx15 is selectively expressed in brown and “brite” adipose tissue. Knockdown organisms show no change in white adipocytes, but do display reduced expression of the marker genes directly involved in brown adipocyte expression.[16]

Tbx15 is noteworthy as a potential marker for cancer, with overexpression being correlated to reduced apoptosis in cancer cells.[17]

Biallelic inactivating variants of the TBX15 gene can cause a recessively inherited condition called Cousin Syndrome. The mutation results in early truncation of the protein, which causes a string of missense amino acids. The resulting protein still has an intact T-box and is still capable of binding to the target DNA sequence in vitro, but it degrades quickly.[18] This condition is associated with short stature, head and facial deformities, and underdevelopment of the shoulder blade and pelvis.[18]

Cousin Syndrome has an equivalent disorder in mice, known as droopy ear; the same mutation of the Tbx15 gene is seen in both species.[18] Droopy ear also results in craniofacial malformations, most abnormal placement and development of the ear. Droopy ear is also associated with abnormal skin color characteristics in mice due to the role of Tbx15's role in establishment of dorsoventral patterning of skin and fur color.[13]