T-box transcription factor TBX15 is protein that is encoded in humans by the Tbx15 gene, mapped to Chromosome 3 in mice [5] 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.[6]
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.[7] Homozygous null embryos display extreme deformities with mesodermal development: the axis of the body is shortened, the notochord fails to form, and posterior somites never develop.[7] Embryonic death occurs around 10 days due to the failure to form the allantois.[7]
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.[8] Tbx15 expression is also seen in limb buds, in the craniofacial region, and in the skin.[9] Failure of expression results in Cousin Syndrome, 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, triggers development glycolytic fast-twitch muscles by the activation of the Akt/PKB signaling pathway.[10]
Effects on embryonic development
editThe 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]
Clinical significance
editBiallelic 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]
References
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000092607 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000027868 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Agulnik SI, Papaioannou VE, Silver LM (July 1998). "Cloning, mapping, and expression analysis of TBX15, a new member of the T-Box gene family". Genomics. 51 (1): 68–75. doi:10.1006/geno.1998.5278. PMID 9693034.
- ^ Herrmann BG (November 1991). "Expression pattern of the Brachyury gene in whole-mount TWis/TWis mutant embryos". Development. 113 (3): 913–917. doi:10.1242/dev.113.3.913. PMID 1821859.
- ^ a b c Herrmann BG, Labeit S, Poustka A, King TR, Lehrach H (February 1990). "Cloning of the T gene required in mesoderm formation in the mouse". Nature. 343 (6259): 617–622. Bibcode:1990Natur.343..617H. doi:10.1038/343617a0. PMID 2154694. S2CID 4365020.
- ^ a b Singh MK, Petry M, Haenig B, Lescher B, Leitges M, Kispert A (February 2005). "The T-box transcription factor Tbx15 is required for skeletal development". Mechanisms of Development. 122 (2): 131–144. doi:10.1016/j.mod.2004.10.011. hdl:11858/00-001M-0000-0012-EA17-1. PMID 15652702. S2CID 15706546.
- ^ Campbell GP, Farkas DR, Chapman DL (May 2022). "Ectopic expression of T in the paraxial mesoderm disrupts somite maturation in the mouse". Developmental Biology. 485: 37–49. doi:10.1016/j.ydbio.2022.02.010. PMID 35276131. S2CID 247357257.
- ^ Omairi S, Matsakas A, Degens H, Kretz O, Hansson KA, Solbrå AV, et al. (August 2016). Cossu, Giulio (ed.). "Enhanced exercise and regenerative capacity in a mouse model that violates size constraints of oxidative muscle fibres". eLife. 5: e16940. doi:10.7554/eLife.16940. PMC 4975572. PMID 27494364.
- ^ Kuijper S, Beverdam A, Kroon C, Brouwer A, Candille S, Barsh G, Meijlink F (April 2005). "Genetics of shoulder girdle formation: roles of Tbx15 and aristaless-like genes". Development. 132 (7): 1601–1610. doi:10.1242/dev.01735. PMID 15728667. S2CID 14618396.
- ^ Farin HF, Lüdtke TH, Schmidt MK, Placzko S, Schuster-Gossler K, Petry M, et al. (2013). "Tbx2 terminates shh/fgf signaling in the developing mouse limb bud by direct repression of gremlin1". PLOS Genetics. 9 (4): e1003467. doi:10.1371/journal.pgen.1003467. PMC 3636256. PMID 23633963.
- ^ a b Candille SI, Van Raamsdonk CD, Chen C, Kuijper S, Chen-Tsai Y, Russ A, et al. (January 2004). "Dorsoventral patterning of the mouse coat by Tbx15". PLOS Biology. 2 (1): E3. doi:10.1371/journal.pbio.0020003. PMC 314463. PMID 14737183.
- ^ Chelbi ST, Doridot L, Mondon F, Dussour C, Rebourcet R, Busato F, et al. (February 2011). "Combination of promoter hypomethylation and PDX1 overexpression leads to TBX15 decrease in vascular IUGR placentas". Epigenetics. 6 (2): 247–255. doi:10.4161/epi.6.2.13791. PMID 20962579. S2CID 25243993.
- ^ a b Gesta S, Bezy O, Mori MA, Macotela Y, Lee KY, Kahn CR (February 2011). "Mesodermal developmental gene Tbx15 impairs adipocyte differentiation and mitochondrial respiration". Proceedings of the National Academy of Sciences of the United States of America. 108 (7): 2771–2776. Bibcode:2011PNAS..108.2771G. doi:10.1073/pnas.1019704108. PMC 3041070. PMID 21282637.
- ^ Gburcik V, Cawthorn WP, Nedergaard J, Timmons JA, Cannon B (October 2012). "An essential role for Tbx15 in the differentiation of brown and "brite" but not white adipocytes" (PDF). American Journal of Physiology. Endocrinology and Metabolism. 303 (8): E1053–E1060. doi:10.1152/ajpendo.00104.2012. PMID 22912368.
- ^ Arribas J, Giménez E, Marcos R, Velázquez A (October 2015). "Novel antiapoptotic effect of TBX15: overexpression of TBX15 reduces apoptosis in cancer cells". Apoptosis. 20 (10): 1338–1346. doi:10.1007/s10495-015-1155-8. PMID 26216026. S2CID 14538236.
- ^ a b c Lausch E, Hermanns P, Farin HF, Alanay Y, Unger S, Nikkel S, et al. (November 2008). "TBX15 mutations cause craniofacial dysmorphism, hypoplasia of scapula and pelvis, and short stature in Cousin syndrome". American Journal of Human Genetics. 83 (5): 649–655. doi:10.1016/j.ajhg.2008.10.011. PMC 2668032. PMID 19068278.