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A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 12; ADAM12

Alternative titles; symbols

MELTRIN-ALPHA, MOUSE, HOMOLOG OF; MLTN

Gene map locus 10q26.3

TEXT

CLONING

To isolate genes related to fertilin expressed in muscle, Yagami-Hiromasa et al. (1995) amplified cDNAs prepared from a mouse myogenic cell line by PCR using degenerative primers for conserved amino acids between fertilin-alpha and -beta (601533). They identified 3 novel mouse sequences, which they called meltrins. Similarly to myogenin, a marker of early muscle differentiation, mouse meltrin-alpha is expressed in neonatal muscle and bone, and its expression increases dramatically in response to the induction of differentiation. Immunocytochemical localization and functional expression studies suggested that meltrin-alpha may be involved in myotube formation.

Gilpin et al. (1998) screened a yeast 2-hybrid cDNA library with laminin beta-2 (150325) cDNA. They isolated a human gene, which they termed ADAM12, that is the human homolog of mouse meltrin-alpha. They found 2 differentially spliced isoforms, a shorter secreted form (ADAM12S) and a larger membrane-bound form (ADAM12L), that diverge at their 3-prime ends. ADAM12L more closely resembles meltrin-alpha; the mature 881-amino acid protein contains a transmembrane domain at its C terminus. The mature ADAM12S 718-amino acid protein has no transmembrane domain. Both forms contain a metalloprotease domain, a disintegrin domain, and a cysteine-rich domain, components characteristic of the ADAM family.

GENE FUNCTION

Galliano et al. (2000) found by RT-PCR and immunoblot analyses that expression of mouse Adam12 increases during muscle regeneration, while the levels of other ADAMs remain constant. Immunofluorescence analysis revealed staining of small, newly formed muscle fibers in regenerating but not normal adult muscle cells. Using a yeast 2-hybrid screen of a human skeletal muscle cDNA library with the cytoplasmic tail of human ADAM12 as bait, Galliano et al. (2000) determined that the membrane proximal portion of the C-terminal half of myristoylated ADAM12 interacts with muscle-specific alpha-actinin-2 (ACTN2; 102573). Galliano et al. (2000) determined that overexpression of cytosolic ADAM12 containing the ACTN2-binding site inhibits mouse myoblast fusion.

MAPPING

Gilpin et al. (1998) used fluorescence in situ hybridization to map the ADAM12 gene to human chromosome 10q26.3. Radiation hybrid mapping placed the gene between markers D10S216 and D10S575. A sequence tagged site (WI-17472) is identical to part of the 3-prime untranslated region of ADAM12.

By FISH, Kurisaki et al. (2003) mapped the mouse Adam12 gene to the F3 distal-F4 band of chromosome 7.

ANIMAL MODEL

By gene targeting, Kurisaki et al. (2003) developed Adam12-deficient mice. Mutant embryos developed at the expected mendelian ratios; however, 30% of the null pups died before weaning. Viable homozygous mutants appeared normal and were fertile. Most muscles of the Adam12-null mice appeared normal, and regeneration in experimentally damaged skeletal muscle was unimpeded. In some Adam12-null pups, the interscapular brown adipose tissue was reduced, although the penetrance of this phenotype appeared low. Impaired formation of the neck and interscapular muscles was also seen in some homozygotes. Kurisaki et al. (2003) hypothesized that Adam12 may be involved in regulating adipogenesis and myogenesis through a linked developmental pathway. They also found that phorbol ester treatment of cultured fibroblasts of null embryos showed reduced ectodomain shedding of heparin-binding epidermal growth factor-like growth factor (HBEGF; 126150), suggesting that this growth factor is a substrate for Adam12.

ADAM12 overexpression had been demonstrated to prevent muscle cell necrosis in the mdx mouse (see DMD, 300377), a model for Duchenne muscular dystrophy (DMD; 310200). Moghadaszadeh et al. (2003) found that transgenic mice overexpressing ADAM12 exhibited only mild myopathic changes and accelerated regeneration following acute injury. Only small changes in gene expression profiles were found between mdx/ADAM12 transgenic mice and mdx mice, suggesting that significant changes in mdx/ADAM12 muscle might occur posttranscriptionally. By immunostaining and immunoblotting, Moghadaszadeh et al. (2003) detected a 2-fold increase in expression and extrasynaptic localization of alpha-7B integrin (ITGA7; 600536) and utrophin (128240), the functional homolog of dystrophin. Expression of dystrophin-associated glycoproteins was also increased.

REFERENCES

1. Galliano, M.-F.; Huet, C.; Frygelius, J.; Polgren, A.; Wewer, U. M.; Engvall, E. :

Binding of ADAM12, a marker of skeletal muscle regeneration, to the muscle-specific actin-binding protein, alpha-actinin-2, is required for myoblast fusion. J. Biol. Chem. 275: 13933-13939, 2000.
PubMed ID : 10788519

2. Gilpin, B. J.; Loechel, F.; Mattei, M.-G.; Engvall, E.; Albrechtsen, R.; Wewer, U. M. :

A novel, secreted form of human ADAM 12 (meltrin alpha) provokes myogenesis in vivo. J. Biol. Chem. 273: 157-166, 1998.
PubMed ID : 9417060

3. Kurisaki, T.; Masuda, A.; Sudo, K.; Sakagami, J.; Higashiyama, S.; Matsuda, Y.; Nagabukuro, A.; Tsuji, A.; Nabeshima, Y.; Asano, M.; Iwakura, Y.; Sehara-Fujisawa, A. :

Phenotypic analysis of meltrin alpha (ADAM12)-deficient mice: involvement of meltrin alpha in adipogenesis and myogenesis. Molec. Cell. Biol. 23: 55-61, 2003.
PubMed ID : 12482960

4. Moghadaszadeh, B.; Albrechtsen, R.; Guo, L. T.; Zaik, M.; Kawaguchi, N.; Borup, R. H.; Kronqvist, P.; Schroder, H. D.; Davies, K. E.; Voit, T.; Nielsen, F. C.; Engvall, E.; Wewer, U. M. :

Compensation for dystrophin-deficiency: ADAM12 overexpression in skeletal muscle results in increased alpha-7 integrin, utrophin and associated glycoproteins. Hum. Molec. Genet. 12: 2467-2479, 2003.
PubMed ID : 12915458

5. Yagami-Hiromasa, T.; Sato, T.; Kurisaki, T.; Kamijo, K.; Nabeshima, Y.; Fujisawa-Sehara, A. :

A metalloprotease-disintegrin participating in myoblast fusion. Nature 377: 652-656, 1995.
PubMed ID : 7566181

CONTRIBUTORS

George E. Tiller - updated : 9/12/2005
Patricia A. Hartz - updated : 3/10/2003
Paul J. Converse - updated : 12/4/2000

CREATION DATE

Jennifer P. Macke : 6/10/1998

EDIT HISTORY

alopez : 9/15/2005
terry : 9/12/2005
terry : 4/5/2005
mgross : 3/12/2003
terry : 3/10/2003
mgross : 12/4/2000
terry : 12/4/2000
alopez : 12/15/1998
alopez : 6/10/1998

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