DEVELOPMENTAL ABNORMALITIES IN MICE TRANSGENIC FOR BOVINE ONCOSTATIN-M

Oncostatin M belongs to the subfamily of hematopoietin cytokines that binds a receptor complex containing gp130. To date, only the human for m of oncostatin M has been identified, and its evolutionary conservati on is unresolved. We have isolated a bovine gene whose open reading fr ame encodes a precursor protein that is 58% identical to human oncosta tin M. A comparison of the bovine and human amino acid sequences predi cts significant similarity, including the four-alpha-helical-bundle st ructure and the placement of disulfide bridges. As with the human prot ein, bovine oncostatin M binds specific receptors on human H2981 cells and inhibits the proliferation of human A375 tumor cells and mouse M1 leukemia cells. To identify activities regulated in vivo, we injected bovine oncostatin M fusion genes containing various tissue-specific p romoters into mouse embryos. The frequencies of transgenic mice were r educed significantly, suggesting that overexpression of the bovine cyt okine is detrimental to normal mouse development. In addition to death s associated with expression in neurons and keratinized epithelia, bov ine oncostatin M caused abnormalities in bone growth and spermatogenes is, stimulated fibrosis surrounding islets in the pancreas, and disrup ted normal lymphoid tissue development. This work establishes the exis tence of a nonprimate oncostatin M gene and provides the first demonst ration that this cytokine can function in a pleiotropic manner in vivo . Information regarding bovine oncostatin M may help characterize the structure and function of this cytokine in other vertebrate species.