Scleraxis

Last updated
scleraxis homolog A (mouse)
Identifiers
SymbolSCXA
NCBI gene 333927
HGNC 24312
OMIM 609067
UniProt Q7RTU7
Other data
Locus Chr. 8 q24.3
scleraxis homolog B (mouse)
Identifiers
SymbolSCXB
NCBI gene 642658
HGNC 32322
RefSeq XM_926116
Other data
Locus Chr. 8 q24.3

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.

Contents

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.

Related Research Articles

Mesoderm Middle germ layer that forms muscle, bone, blood vessels and more

The mesoderm is the middle layer of the three germ layers that develop during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.

Somite Each of several blocks of mesoderm that flank the neural tube on either side in embryogenesis

The somites 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 into the sclerotomes, myotomes, syndetomes and dermatomes that give rise to the vertebrae of the vertebral column, rib cage and part of the occipital bone; skeletal muscle, cartilage, tendons, and skin.

Basic helix–loop–helix Protein structural motif

A basic helix–loop–helix (bHLH) is a protein structural motif that characterizes one of the largest families of dimerizing transcription factors. The word "basic" does not refer to complexity but to the chemistry of the motif because transcription factors in general contain basic amino acid residues in order to facilitate DNA binding.

Sterol regulatory element-binding protein Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

Myogenesis Formation of muscular tissue, particularly during embryonic development

Myogenesis is the formation of skeletal muscular tissue, particularly during embryonic development.

Myogenin Mammalian protein found in Homo sapiens

Myogenin, is a transcriptional activator encoded by the MYOG gene. Myogenin is a muscle-specific basic-helix-loop-helix (bHLH) transcription factor involved in the coordination of skeletal muscle development or myogenesis and repair. Myogenin is a member of the MyoD family of transcription factors, which also includes MyoD, Myf5, and MRF4.

Mef2

In the field of molecular biology, myocyte enhancer factor-2 (Mef2) proteins are a family of transcription factors which through control of gene expression are important regulators of cellular differentiation and consequently play a critical role in embryonic development. In adult organisms, Mef2 proteins mediate the stress response in some tissues. Mef2 proteins contain both MADS-box and Mef2 DNA-binding domains.

The gene extramachrochaetae (emc) is a Drosophila melanogaster gene that codes for the Emc protein, which has a wide variety of developmental roles. It was named, as is common for Drosophila genes, after the phenotypic change caused by a mutation in the gene.

ID1 Protein-coding gene in the species Homo sapiens

DNA-binding protein inhibitor ID-1 is a protein that in humans is encoded by the ID1 gene.

ID3 (gene) Protein-coding gene in the species Homo sapiens

DNA-binding protein inhibitor ID-3 is a protein that in humans is encoded by the ID3 gene.

TCF12

Transcription factor 12 is a protein that in humans is encoded by the TCF12 gene.

HES1 Protein-coding gene in the species Homo sapiens

Transcription factor HES1 is a protein that is encoded by the Hes1 gene, and is the mammalian homolog of the hairy gene in Drosophila. HES1 is one of the seven members of the Hes gene family (HES1-7). Hes genes code nuclear proteins that suppress transcription.

HEY1 Protein-coding gene in the species Homo sapiens

Hairy/enhancer-of-split related with YRPW motif protein 1 is a protein that in humans is encoded by the HEY1 gene.

HEY2 Protein-coding gene in the species Homo sapiens

Hairy/enhancer-of-split related with YRPW motif protein 2 (HEY2) also known as cardiovascular helix-loop-helix factor 1 (CHF1) is a protein that in humans is encoded by the HEY2 gene.

ID4 Protein-coding gene in humans

ID4 is a protein coding gene. In humans, it encodes for the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesis. This is inclusive of embryonic cellular growth, senescence, cellular differentiation, apoptosis, and as an oncogene in angiogenesis.

HAND1

Heart- and neural crest derivatives-expressed protein 1 is a protein that in humans is encoded by the HAND1 gene.

TCF21 (gene)

Transcription factor 21 (TCF21), also known as pod-1, capsuling, or epicardin, is a protein that in humans is encoded by the TCF21 gene on chromosome 6. It is ubiquitously expressed in many tissues and cell types and highly significantly expressed in lung and placenta. TCF21 is crucial for the development of a number of cell types during embryogenesis of the heart, lung, kidney, and spleen. TCF21 is also deregulated in several types of cancers, and thus known to function as a tumor suppressor. The TCF21 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

BHLHE41 Protein-coding gene in the species Homo sapiens

"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.

MYF5 Protein-coding gene in the species Homo sapiens

Myogenic factor 5 is a protein that in humans is encoded by the MYF5 gene. It is a protein with a key role in regulating muscle differentiation or myogenesis, specifically the development of skeletal muscle. Myf5 belongs to a family of proteins known as myogenic regulatory factors (MRFs). These basic helix loop helix transcription factors act sequentially in myogenic differentiation. MRF family members include Myf5, MyoD (Myf3), myogenin, and MRF4 (Myf6). This transcription factor is the earliest of all MRFs to be expressed in the embryo, where it is only markedly expressed for a few days. It functions during that time to commit myogenic precursor cells to become skeletal muscle. In fact, its expression in proliferating myoblasts has led to its classification as a determination factor. Furthermore, Myf5 is a master regulator of muscle development, possessing the ability to induce a muscle phenotype upon its forced expression in fibroblastic cells.

Proneural genes encode transcription factors of the basic helix-loop-helix (bHLH) class which are responsible for the development of neuroectodermal progenitor cells. Proneural genes have multiple functions in neural development. They integrate positional information and contribute to the specification of progenitor-cell identity. From the same ectodermal cell types, neural or epidermal cells can develop based on interactions between proneural and neurogenic genes. Neurogenic genes are so called because loss of function mutants show an increase number of developed neural precursors. On the other hand, proneural genes mutants fail to develop neural precursor cells.

References

  1. 1 2 3 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. doi:10.1242/dev.121.4.1099. 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. S2CID   16291509.
  3. 1 2 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. 1 2 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. Bibcode:1993PNAS...90.8305J. 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. Bibcode:1997PNAS...94.5172A. 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.
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