T-box transcription factor TBX15 is

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that is encoded in humans by the Tbx15

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

, mapped to Chromosome 3 in mice and Chromosome 1 in humans. Tbx15 is a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

that plays a key role in embryonic development. Like other members of the

T-box 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 an ...

subfamily, Tbx15 is expressed in the

notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consis ...

and

primitive streak The primitive streak is a structure that forms in the early embryo in amniotes. In amphibians the equivalent structure is the blastopore. During early embryonic development, the embryonic disc becomes oval shaped, and then pear-shaped with the ...

, where it assists with the formation and differentiation of the mesoderm. It is steadily downregulated after segmentation of the

paraxial mesoderm Paraxial mesoderm, also known as presomitic or somitic mesoderm is the area of mesoderm in the neurulating embryo that flanks and forms simultaneously with the neural tube. The cells of this region give rise to somites, blocks of tissue running ...

. Expression of the T-box overall is a requirement for an embryo to remain viable. Heterozygous T-null mutations in mice result in short tails and some defects in sacral vertebrae. Homozygous null embryos display extreme deformities with mesodermal development: the axis of the body is shortened, the notochord fails to form, and posterior

somites The somites (outdated term: primitive segments) are a set of bilaterally paired blocks of paraxial mesoderm that form in the embryonic stage of somitogenesis, along the head-to-tail axis in segmented animals. In vertebrates, somites subdivide in ...

never develop. Embryonic death occurs around 10 days due to the failure to form the

allantois The allantois (plural ''allantoides'' or ''allantoises'') is a hollow sac-like structure filled with clear fluid that forms part of a developing amniote's conceptus (which consists of all embryonic and extraembryonic tissues). It helps the embryo ...

. Tbx15 plays a relatively minor role within this family. Tbx15 plays a role in the development of the skeleton. it is mainly associated with the development of the limbs, spinal column, and head. In particular, Tbx15 is shown to influence the development of the scapula or shoulder blade. Tbx15 expression is also seen in limb buds, in the craniofacial region, and in the skin. Failure of expression results in

Cousin Syndrome Cousin syndrome is a genetic condition characterized by short stature at birth, a short neck with low-positioned external ears, as well as congenital malformations of the skeletal system affecting the shoulders, the pelvis, the neck, and the limbs ...

, a disorder characterized by defects in craniofacial development and malformation of the shoulder girdle. The effects of Tbx15 are also demonstrated in regulation of adipocyte differentiation, positional regulation of the dorsolateral mesenchyme, and growth of mitochondria. Tbx15, together with

SMARCD3 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 is a protein that in humans is encoded by the ''SMARCD3'' gene. Function The protein encoded by this gene is a member of the SWI/SNF family of protei ...

, triggers development

glycolytic Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...

fast-twitch muscles by the activation of the

Akt/PKB signaling pathway The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K (phosphatidylinositol 3-kinase) and Akt ( protein kinas ...

Effects on embryonic development

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. 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. 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 The PAX3 (paired box gene 3) gene encodes a member of the paired box or PAX family of transcription factors. The PAX family consists of nine human (PAX1-PAX9) and nine mouse (Pax1-Pax9) members arranged into four subfamilies. Human PAX3 and mouse ...

is deactivated as well. 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. This reflects Tbx15’s role in determining the limb dorsoventral boundary during early fetal development rather than any direct influence on the

ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...

. 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 In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...

of Tbx15 plays a role in overall fetal growth, with hypomethylation having a demonstrable effect on placental functioning. Vascular

intrauterine growth restriction Intrauterine growth restriction (IUGR), or fetal growth restriction, refers to poor growth of a fetus while in the womb during pregnancy. IUGR is defined by clinical features of malnutrition and evidence of reduced growth regardless of an infant's ...

follows, and it may have a correlation with increased rates of

preeclampsia Pre-eclampsia is a disorder of pregnancy characterized by the onset of high blood pressure and often a significant amount of protein in the urine. When it arises, the condition begins after 20 weeks of pregnancy. In severe cases of the disease ...

. Tbx15 also down-regulates the mass of mitochondria and the rate of basal mitochondrial expression, with both decreasing significantly if the gene is overexpressed. Tbx15 plays a role in

adipocyte Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...

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. 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. Tbx15 is noteworthy as a potential marker for cancer, with overexpression being correlated to reduced

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...

in cancer cells.

Clinical significance

Biallelic inactivating variants of the TBX15 gene can cause a recessively inherited condition called

. The mutation results in early truncation of the protein, which causes a string of

missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense mu ...

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. This condition is associated with short stature, head and facial deformities, and underdevelopment of the shoulder blade and pelvis. Cousin Syndrome has an equivalent disorder in mice, known as droopy ear; the same mutation of the Tbx15 gene is seen in both species. 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.

References

{{Reflist Transcription factors