Phenotypic Analysis of Meltrin α (ADAM12)-Deficient Mice: Involvement of Meltrin α in Adipogenesis and Myogenesis

Abstract

Meltrin α (ADAM12) is a metalloprotease-disintegrin whose specific expression patterns during development suggest that it is involved in myogenesis and the development of other organs. To determine the roles Meltrin α plays in vivo, we generated Meltrin α-deficient mice by gene targeting. Although the number of homozygous embryos are close to the expected Mendelian ratio at embryonic days 17 to 18, ca. 30% of the null pups born die before weaning, mostly within 1 week of birth. The viable homozygous mutants appear normal and are fertile. Most of the muscles in the homozygous mutants appear normal, and regeneration in experimentally damaged skeletal muscle is unimpeded. In some Meltrin α-deficient pups, the interscapular brown adipose tissue is reduced, although the penetrance of this phenotype is low. Impaired formation of the neck and interscapular muscles is also seen in some homozygotes. These observations suggest Meltrin α may be involved in regulating adipogenesis and myogenesis through a linked developmental pathway. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a candidate substrate of Meltrin α, and we found that TPA (12-O-tetradecanoylphorbol-13-acetate)-induced ectodomain shedding of HB-EGF is markedly reduced in embryonic fibroblasts prepared from Meltrin α-deficient mice. We also report here the chromosomal locations of Meltrin α in the mouse and rat.

ACKNOWLEDGMENTS

This work was supported in part by a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology and by research grants from the Japanese Health Science Foundation, the National Center of Neurology and Psychiatry of the Ministry of Health and Welfare of Japan, and CREST (Core Research for Evolutional Science and Technology) of the Japan Science and Technology Corporation.

We thank T. Obata for technical assistance, T. Fujimori for helpful comments, and R. T. Yu for critically reading the manuscript.