In the course of examining the Drosophila tumor suppressor gene (Dlg), scientists at the Helmholtz Zentrum München have succeeded in decoding a new mechanism that regulates cell polarity in epithelial tissues or in neurons in the brain. The findings, which are presented in the current issue of Developmental Cell, will help to enhance the understanding of how metastases and mental retardation occur and enable targeted, long-term therapeutic approaches to their treatment to be developed.
Mutations of the Dlg tumor suppressor gene trigger cancer and metastases in fruit flies, and mental retardation in mammals. A team of scientists headed by Professor Heiko Lickert from the Institute for Stem Cell Research at the Helmholtz Center Munich working in cooperation with colleagues from the Department for Protein Analysis and the Institute for Toxicology has now discovered why the Dlg gene family has gained other evolutionary functions.
Fruit flies possess a copy of the Dlg gene, which plays a role in regulating cell proliferation and basolateral epithelial polarity. Mammals possess four copies of the Dlg gene which have developed in different ways. As a result of these changes, Dlg3 has assumed a new function. It is responsible for the apical alignment of cells and acts as a structural protein to stabilize tight junctionsThis new function is due to minor changes in the sequence of amino acids of the protein produced by the Dlg3 gene. These promote interaction with other proteins and, as a result, make it possible to determine and maintain the alignment of the apical side of the cell.
In the event of a mutation, this new function of the Dlg3 gene in mammals could alter the tissue structure of the Spemann/Mangold organizer, which plays a pivotal role in neural induction and normal brain development. Previous studies have shown that mutations in the human Dlg3 gene go hand-in-hand with mental retardation. The scientists could therefore have discovered the cause of this disorder, which also plays a decisive role in humans and which they could use as a target for new therapies and active substances. Follow-up studies will help to explain the mechanism in greater detail because "the more we know about the mechanisms that lead to the loss of cell polarity and the formation of metastases, the better able we will be to develop new approaches to therapies and active substances," Professor Lickert says.