LFNG

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Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe, also known as Lunatic Fringe, is a protein encoded in humans by the LFNG gene. [1] [2] [3]

Contents

LFNG
Identifiers
Aliases LFNG , SCDO3, LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase
External IDs OMIM: 602576 MGI: 1095413 HomoloGene: 22475 GeneCards: LFNG
Orthologs
SpeciesHumanMouse
Entrez

3955

16848

Ensembl

ENSG00000106003

ENSMUSG00000029570

UniProt

Q8NES3

O09010

RefSeq (mRNA)

NM_002304
NM_001040167
NM_001040168
NM_001166355

NM_008494

RefSeq (protein)

NP_001035257
NP_001035258
NP_001159827
NP_002295

NP_032520

Location (UCSC) Chr 7: 2.51 – 2.53 Mb Chr 5: 140.59 – 140.6 Mb
PubMed search [6] [7]
Wikidata
View/Edit Human View/Edit Mouse

This gene encodes a member of the glycosyltransferase superfamily. The encoded protein is a single-pass type II Golgi membrane protein that functions as a fucose-specific glycosyltransferase, adding an N-acetylglucosamine to the fucose residue of a group of signaling receptors involved in regulating cell fate decisions during development. Mutations in this gene have been associated with autosomal recessive spondylocostal dysostosis 3. Alternatively spliced transcript variants that encode different isoforms have been described, however, not all variants have been fully characterized. [3]

Function

LFNG is a gene whose role in embryonic development is to establish the anterior boundary of somites, which will eventually develop in vertebrae, ribs, and dermis. [8] Lunatic Fringe responds to certain threshold ratios of retinoic acid and FGF-8 in order to mark the anterior boundary of somites while another transcription factor, Hairy, responds to different threshold ratios of retinoic acid and FGF-8 to form the posterior boundaries of somites. [9]

Clinical significance

A defect associated with Lfng mutations is spondylocostal dysostosis. Spondylocostal dysostosis is characterized by segmentation problems in the developing vertebrae resulting in fusion or lack of vertebrae along with abnormalities in the ribs. [10] Clinically, spondylocostal dysostosis presents as a shortened neck and trunk relative total height and a mild form of scoliosis. Respiratory problems are also common in spondylocostal dysostosis because of the shortened trunk.

A knockout model for Lfng has been created in mice, and without Lfng, mice have shorter tails, and impaired rib, lung, and somite development. A deficiency of Lfng in male mice has also been associated with lack of spermatozoa in the epididymis of many mice; however, spermatogenesis was not impaired. Rather, the male mice were subfertile. [11] In female mice, Lfng deficiency led to infertility because of abnormal folliculogenesis. Further examination showed that oocytes from these female mice did not complete meiotic maturation. [12] However, there are other studies that contradict this stating that not all female mice deficient of Lfng are infertile. A possible explanation for this difference between these studies is that the Lfng alleles were functional different, however, this is unlikely. More likely is that this discrepancy results from differences in the genetic background of the mice or husbandry and colony conditions. [13]

Impact of mutation

Lunatic Fringe is a transcription factor that plays a crucial role in the development of the somites. Somites give rise to the skeletal muscle, the axial skeleton, the tendons, and the dorsal dermis. The somites are formed via the clock-wave front model, and as each somite is formed, each cell receives a burst of FGF8 (a signaling molecule). Somites are formed anterior to posterior, and since FGF8 has a short half-life, this leads to a greater concentration of FGF8 in the posterior, and a lesser concentration in the anterior. Lunatic fringe responds to the lower concentration of FGF8 in the anterior and leads these cells to their developmental fate. Mutation of the Lunatic Fringe gene can cause severe spondylocostal dysostosis, which involves vertebral segmentation defects and rib abnormalities. A mutation was discovered in which a conservative phenylalanine close to the active site of the enzyme mutates, leading to the enzymatic inactivation of Lunatic Fringe. A “knock-out” model has been created using mice. In mice, Lunatic Fringe plays a crucial role in the Notch signaling pathway during the formation of somites, and a mutation in this gene leads to somites with irregular shapes and a defect in the anterior-posterior formation. [10] [14]

Related Research Articles

<span class="mw-page-title-main">Notch signaling pathway</span> Series of molecular signals

The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

Fringe genes are important in the workings of the notch signaling pathway.

<span class="mw-page-title-main">Retinoic acid</span> Metabolite of vitamin A

Retinoic acid (used simplified here for all-trans-retinoic acid) is a metabolite of vitamin A1 (all-trans-retinol) that mediates the functions of vitamin A1 required for growth and development. All-trans-retinoic acid is required in chordate animals, which includes all higher animals from fish to humans. During early embryonic development, all-trans-retinoic acid generated in a specific region of the embryo helps determine position along the embryonic anterior/posterior axis by serving as an intercellular signaling molecule that guides development of the posterior portion of the embryo. It acts through Hox genes, which ultimately control anterior/posterior patterning in early developmental stages.

<span class="mw-page-title-main">Intermediate mesoderm</span> Layer of cells in mammalian embryos

Intermediate mesoderm or intermediate mesenchyme is a narrow section of the mesoderm located between the paraxial mesoderm and the lateral plate of the developing embryo. The intermediate mesoderm develops into vital parts of the urogenital system.

The limb bud is a structure formed early in vertebrate limb development. As a result of interactions between the ectoderm and underlying mesoderm, formation occurs roughly around the fourth week of development. In the development of the human embryo the upper limb bud appears in the third week and the lower limb bud appears four days later.

In enzymology, an O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase is an enzyme that catalyzes the chemical reaction in which a beta-D-GlcNAc residue is transferred from UDP-D-GlcNAc to the fucose residue of a fucosylated protein.

<span class="mw-page-title-main">Forkhead box C1</span> Protein-coding gene in the species Homo sapiens

Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the FOXC1 gene.

<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.

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

Beta-1,3-N-acetylglucosaminyltransferase manic fringe is an enzyme that in humans is encoded by the MFNG gene, a member of the fringe gene family which also includes the radical fringe (RFNG) and lunatic fringe (LFNG).

<i>EN1</i> (gene) Protein-coding gene in the species Homo sapiens

Homeobox protein engrailed-1 is a protein that in humans is encoded by the EN1 gene.

<span class="mw-page-title-main">DLL3</span> Protein-coding gene in the species Homo sapiens

Delta-like 3 (Drosophila), also known as DLL3, is a protein which in humans is encoded by the DLL3 gene. Two transcript variants encoding distinct isoforms have been identified for this gene.

<span class="mw-page-title-main">GBX2</span> Protein-coding gene in the species Homo sapiens

Homeobox protein GBX-2 is a protein that in humans is encoded by the GBX2 gene.

<span class="mw-page-title-main">VAX1</span> Protein-coding gene in the species Homo sapiens

Ventral anterior homeobox 1 is a protein that in humans is encoded by the VAX1 gene.

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

Mesoderm posterior protein 2 (MESP2), also known as class C basic helix-loop-helix protein 6 (bHLHc6), is a protein that in humans is encoded by the MESP2 gene.

Segmentation is the physical characteristic by which the human body is divided into repeating subunits called segments arranged along a longitudinal axis. In humans, the segmentation characteristic observed in the nervous system is of biological and evolutionary significance. Segmentation is a crucial developmental process involved in the patterning and segregation of groups of cells with different features, generating regional properties for such cell groups and organizing them both within the tissues as well as along the embryonic axis.

<span class="mw-page-title-main">HES7 gene</span> Protein-coding gene in humans

(HES7) or bHLHb37 is protein coding mammalian gene found on chromosome 17 in humans. HES7 is a member of the Hairy and Enhancer of Split families of Basic helix-loop-helix proteins. The gene product is a transcription factor and is expressed cyclically in the presomitic mesoderm as part of the Notch signalling pathway. HES7 is involved in the segmentation of somites from the presomitic mesoderm in vertebrates. The HES7 gene is self-regulated by a negative feedback loop in which the gene product can bind to its own promoter. This causes the gene to be expressed in an oscillatory manner. The HES7 protein also represses expression of Lunatic Fringe (LFNG) thereby both directly and indirectly regulating the Notch signalling pathway. Mutations in HES7 can result in deformities of the spine, ribs and heart. Spondylocostal dysostosis is a common disease caused by mutations in the HES7 gene. The inheritance pattern of Spondylocostal dysostosis is autosomal recessive.

<span class="mw-page-title-main">CDX4 (gene)</span> Protein-coding gene in humans

Homeobox protein CDX-4 is a protein that in humans is encoded by the CDX4 gene. This gene is a member of the caudal-related homeobox transcription factor family that also includes CDX1 and CDX2.

<span class="mw-page-title-main">TBX15</span> Human protein and coding gene

T-box transcription factor TBX15 is protein that is encoded in humans by the Tbx15 gene, mapped to Chromosome 3 in mice 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.

<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.

<span class="mw-page-title-main">Kenro Kusumi</span> Genome biologist and professor at Arizona State University

Kenro Kusumi, a genome biologist and professor, Dean of Natural Sciences in The College of Liberal Arts and Sciences at Arizona State University.

References

  1. ↑ "LFNG - Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe - Homo sapiens (Human) - LFNG gene & protein". www.uniprot.org. Retrieved 4 June 2022.
  2. ↑ Egan S, Herbrick JA, Tsui LC, Cohen B, Flock G, Beatty B, Scherer SW (December 1998). "Mapping of the human Lunatic Fringe (LFNG) gene to 7p22 and Manic Fringe (MFNG) to 22q12". Genomics. 54 (3): 576–7. doi:10.1006/geno.1998.5559. PMID   9878264.
  3. 1 2 "Entrez Gene: LFNG LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase".
  4. 1 2 3 GRCh38: Ensembl release 89: ENSG00000106003 – Ensembl, May 2017
  5. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000029570 – Ensembl, May 2017
  6. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  7. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  8. ↑ Serth K, Schuster-Gossler K, Cordes R, Gossler A (April 2003). "Transcriptional oscillation of lunatic fringe is essential for somitogenesis". Genes & Development. 17 (7): 912–25. doi:10.1101/gad.250603. PMC   196028 . PMID   12670869.
  9. ↑ Shifley ET, Vanhorn KM, Perez-Balaguer A, Franklin JD, Weinstein M, Cole SE (March 2008). "Oscillatory lunatic fringe activity is crucial for segmentation of the anterior but not posterior skeleton". Development. 135 (5): 899–908. doi:10.1242/dev.006742. PMID   18234727. S2CID   37267418.
  10. 1 2 Sparrow DB, Chapman G, Wouters MA, Whittock NV, Ellard S, Fatkin D, Turnpenny PD, Kusumi K, Sillence D, Dunwoodie SL (January 2006). "Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype". American Journal of Human Genetics. 78 (1): 28–37. doi:10.1086/498879. PMC   1380221 . PMID   16385447.
  11. ↑ Hahn KL, Beres B, Rowton MJ, Skinner MK, Chang Y, Rawls A, Wilson-Rawls J (January 2009). "A deficiency of lunatic fringe is associated with cystic dilation of the rete testis". Reproduction. 137 (1): 79–93. doi:10.1530/REP-08-0207. PMC   5739036 . PMID   18801836.
  12. ↑ Hahn KL, Johnson J, Beres BJ, Howard S, Wilson-Rawls J (February 2005). "Lunatic fringe null female mice are infertile due to defects in meiotic maturation". Development. 132 (4): 817–28. doi: 10.1242/dev.01601 . PMID   15659488.
  13. ↑ Xu J, Norton CR, Gridley T (February 2006). "Not all lunatic fringe null female mice are infertile". Development. 133 (4): 579, author reply 579–80. doi: 10.1242/dev.02221 . PMID   16436621.
  14. ↑ Zhang N, Gridley T (July 1998). "Defects in somite formation in lunatic fringe-deficient mice". Nature. 394 (6691): 374–7. Bibcode:1998Natur.394..374Z. doi:10.1038/28625. PMID   9690472. S2CID   4423185.

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