Strikingly, their study shows that, in Drosophila embryos, mir-1 expression is not required for mesodermal cell fate decisions or cell proliferation during embryogenesis, but rather, that it appears to act to reinforce and maintain cell identity during times of rapid growth.

The authors find that, as in zebrafish, mouse and humans, Dmir-1 is specifically expressed in muscle cells. Furthermore, they show that Dmir-1 expression is regulated by the promesodermal transcription factor Twist and the promyogenic transcription factor Mef2, thus placing Dmir-1 within established transcriptional networks in muscle. However, the authors find that muscles form normally in embryos in which expression of Dmir-1 has been ablated by gene targeting (Dmir-1 KO). A defect is only revealed when larval growth is initiated by feeding, which triggers paralysis and eventually death of Dmir-1 KO larvae.

Analysis of the mutant larvae after feeding reveals disrupted somatic musculature, strongly suggesting a role for Dmir-1 in the maintenance of muscle integrity and identity in times of stress induced by growth. Dr. Sokol proposes that "Mir-1 could function generally to maintain muscle cell identity by ensuring that mRNAs from promiscuously transcribed nonmuscle genes remain inactive." Their work adds to the emerging range of functions that miRNAs perform in an organism and advocates the study of loss-of-function mutations in miRNA genes as an essential tool for identifying the biological roles of miRNAs.

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"Because a loss of MGMT protein function is a plausible predisposing factor for cancer through the increased occurrence of mutations , our data indicate that MGMT promoter methylation may qualify as a marker of the field defect in colorectal cancer," the authors write. In addition, "given the high lifetime risk of colorectal tumor development in the U.S. population, it is reasonable to propose testing to determine whether healthy persons with MGMT promoter methylation in normal colorectal mucosa are at higher risk of developing a colon tumor than those without such methylation."

In an editorial, Edward Giovannucci, M.D., Sc.D., of the Harvard School of Public Health, and Shuji Ogino, of Brigham and Women's Hospital, both in Boston, review the concept of the field defect (also called the field effect or field cancerization). They also raise several questions about how these findings may affect related areas of research, such as approaches to chemoprevention and "whether the reversal of DNA methylation in precancerous cells may prevent the development of new primary cancers in the same organ," they write.

jncicancerspectrum.oupjournals/