TBX15

Last updated
TBX15
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TBX15 , TBX14, T-box 15, T-box transcription factor 15
External IDs OMIM: 604127 MGI: 1277234 HomoloGene: 7967 GeneCards: TBX15
Orthologs
SpeciesHumanMouse
Entrez

6913

21384

Ensembl

ENSG00000092607

ENSMUSG00000027868

UniProt

Q96SF7

O70306

RefSeq (mRNA)

NM_152380
NM_001330677

NM_009323

RefSeq (protein)

NP_001317606
NP_689593

NP_033349

Location (UCSC) Chr 1: 118.88 – 118.99 Mb Chr 3: 99.15 – 99.26 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Contents

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

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]

Clinical significance

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]

Related Research Articles

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<span class="mw-page-title-main">T-box</span> Group of proteins containing a T-box domain

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<i>TBX5</i> (gene) Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Fibroblast growth factor 8</span> Protein-coding gene in the species Homo sapiens

Fibroblast growth factor 8(FGF-8) is a protein that in humans is encoded by the FGF8 gene.

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<span class="mw-page-title-main">TBX2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">PRRX1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">OSR1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TBX22</span> Protein-coding gene in the species Homo sapiens

T-box transcription factor TBX22 is a protein that in humans is encoded by the TBX22 gene.

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<span class="mw-page-title-main">NKX3-2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">MESP2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">KLF15</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">TBX6</span> Protein-coding gene in the species Homo sapiens

T-box 6 is a protein that in humans is encoded by the TBX6 gene.

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.

<span class="mw-page-title-main">Beta-1,3-N-acetylglucosaminyltransferase radical fringe</span> Protein-coding gene in the species Homo sapiens

Beta-1,3-N-acetylglucosaminyltransferase radical fringe, also known as radical fringe is a protein that in humans is encoded by the RFNG gene. Radical fringe is a signaling enzyme involved in the arrangement of the embryonic limb buds. It is a member of the fringe gene family, which also includes manic fringe and lunatic fringe. It is important for the dorsoventrally patterning of the limb and has been implicated in the formation of the apical ectodermal ridge (AER). The AER is essential for the distal patterning of the limb. Experiments executed in chicken models show Radical fringe is expressed in both the dorsal ectoderm and the AER. This provides evidence that the AER forms from cells already expressing radical fringe, though further evidence is needed to confirm. Grafting experiments have shown that formation of the AER comes from signals in the limb bud mesoderm. However, radical fringe acts as a permissive signal to create a boundary for the AER to form. The knockout experiments done in chicken models suggest Radical fringe plays an integral role in wing development.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000092607 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027868 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ 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.
  6. ↑ 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.
  7. 1 2 3 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.
  8. 1 2 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. 1 2 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.
  14. ↑ 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.
  15. 1 2 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.
  16. ↑ 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.
  17. ↑ 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.
  18. 1 2 3 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.
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