Scleraxis

The scleraxis protein is a member of the basic helix-loop-helix (bHLH) superfamily of transcription factors.[1] Currently two genes (SCXA and SCXB respectively) have been identified to code for identical scleraxis proteins.

scleraxis homolog A (mouse)
Identifiers
Symbol	SCXA
NCBI gene	333927
HGNC	24312
OMIM	609067
UniProt	Q7RTU7
Other data
Locus	Chr. 8 q24.3

scleraxis homolog B (mouse)
Identifiers
Symbol	SCXB
NCBI gene	642658
HGNC	32322
RefSeq	XM_926116
Other data
Locus	Chr. 8 q24.3

Function

It is thought that early scleraxis-expressing progenitor cells lead to the eventual formation of tendon tissue and other muscle attachments.[1] Scleraxis is involved in mesoderm formation and is expressed in the syndetome (a collection of embryonic tissue that develops into tendon and blood vessels) of developing somites (primitive segments or compartments of embryos).[2]

Inducing scleraxis expression

The syndetome location within the somite is determined by FGF secreted from the center of the myotome (a collection of embryonic tissue that develops into skeletal muscle)- the FGF then induces the adjacent anterior and posterior sclerotome (a collection of embryonic tissue that develops into the axial skeleton) to adopt a tendon cell fate. This ultimately places future scleraxis-expressing cells between the two tissue types they will ultimately join. [3]

Scleraxis expression will be seen throughout the entire sclerotome (rather than just the sclerotome directly anterior and posterior to the myotome) with an overexpression of FGF8, demonstrating that all sclerotome cells are capable of expressing scleraxis in response to FGF signaling. While the FGF interaction has been shown to be necessary for scleraxis expression, it is still unclear as to whether the FGF signaling pathway directly induces the syndetome to secrete scleraxis, or indirectly through a secondary signaling pathway. Most likely, the syndetomal cells, through careful reading of the FGF concentration (coming from the myotome), can precisely determine their location and begin expressing scleraxis.[3] Much of embryonic development follows this model of inducing specific cell fates through the reading of surrounding signaling molecule concentration gradients.

Background

bHLH transcription factors have been shown to have a wide array of functions in developmental processes.[4] More precisely, they have critical roles in the control of cellular differentiation, proliferation and regulation of oncogenesis.[4][5][6] To date, 242 eukaryotic proteins belonging to the HLH superfamily have been reported. They have varied expression patterns in all eukaryotes from yeast to humans.[7]

Structurally, bHLH proteins are characterised by a “highly conserved domain containing a stretch of basic amino acids adjacent to two amphipathic α-helices separated by a loop”.[8][9]

These helices have important functional properties, forming part of the DNA binding and transcription activating domains. With respect to scleraxis, the bHLH region spans amino acid residues 78 to 131. A proline rich region is also predicted to lie between residues 161–170. A stretch of basic residues, which aids in DNA binding, is found closer to the N terminal end of scleraxis.[1][10]

HLH proteins that lack this basic domain have been shown to negatively regulate the activities of bHLH proteins and are called inhibitors of differentiation (Id).[11] Basic HLH proteins function normally as dimers and bind to a specific hexanucleotide DNA sequence (CAANTG) known as an E-box thus switching on the expression of various genes involved in cellular development and survival.

References

1. Cserjesi P, Brown D, Ligon KL, Lyons GE, Copeland NG, Gilbert DJ, Jenkins NA, Olson EN (April 1995). "Scleraxis: a basic helix-loop-helix protein that prefigures skeletal formation during mouse embryogenesis". Development. 121 (4): 1099–110. PMID 7743923.
2. Brent AE, Schweitzer R, Tabin CJ (April 2003). "A somitic compartment of tendon progenitors". Cell. 113 (2): 235–48. doi:10.1016/S0092-8674(03)00268-X. PMID 12705871.
3. Brent AE, Tabin CJ (August 2004). "FGF acts directly on the somitic tendon progenitors through the Ets transcription factors Pea3 and Erm to regulate scleraxis expression". Development. 131 (16): 3885–96. doi:10.1242/dev.01275. PMID 15253939.
4. Kadesch T (January 1993). "Consequences of heteromeric interactions among helix-loop-helix proteins". Cell Growth & Differentiation. 4 (1): 49–55. PMID 8424906.
5. Olson EN, Klein WH (January 1994). "bHLH factors in muscle development: dead lines and commitments, what to leave in and what to leave out". Genes & Development. 8 (1): 1–8. doi:10.1101/gad.8.1.1. PMID 8288123.
6. Jan YN, Jan LY (September 1993). "Functional gene cassettes in development". Proceedings of the National Academy of Sciences of the United States of America. 90 (18): 8305–7. doi:10.1073/pnas.90.18.8305. PMC 47343. PMID 8378299.
7. Atchley WR, Fitch WM (May 1997). "A natural classification of the basic helix-loop-helix class of transcription factors". Proceedings of the National Academy of Sciences of the United States of America. 94 (10): 5172–6. doi:10.1073/pnas.94.10.5172. PMC 24651. PMID 9144210.
8. Wilson-Rawls J, Rhee JM, Rawls A (September 2004). "Paraxis is a basic helix-loop-helix protein that positively regulates transcription through binding to specific E-box elements". The Journal of Biological Chemistry. 279 (36): 37685–92. doi:10.1074/jbc.M401319200. PMID 15226298.
9. Ellenberger T, Fass D, Arnaud M, Harrison SC (April 1994). "Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer". Genes & Development. 8 (8): 970–80. doi:10.1101/gad.8.8.970. PMID 7926781.
10. Wolf C, Thisse C, Stoetzel C, Thisse B, Gerlinger P, Perrin-Schmitt F (February 1991). "The M-twist gene of Mus is expressed in subsets of mesodermal cells and is closely related to the Xenopus X-twi and the Drosophila twist genes". Developmental Biology. 143 (2): 363–73. doi:10.1016/0012-1606(91)90086-I. PMID 1840517.
11. Jen Y, Manova K, Benezra R (November 1996). "Expression patterns of Id1, Id2, and Id3 are highly related but distinct from that of Id4 during mouse embryogenesis". Developmental Dynamics. 207 (3): 235–52. doi:10.1002/(SICI)1097-0177(199611)207:3<235::AID-AJA1>3.0.CO;2-I. PMID 8922523.