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 junctions*. This 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.
*Dlg gene: tumor suppressor that controls cell proliferation and cell polarity. If it is mutated, it causes neoplastic tumors, i.e. cells proliferate in an unregulated manner, lose their polarity and as a result metastasize. Fruit flies only possess a copy of the Dlg gene. In mammals, the Dlg gene family encompasses four genes.
*Cell proliferation: increase in cells through cell growth and cell division.
* Apical/ basal/ lateral cell polarity: local alignment of a cell in the epithelium. Apical refers to the outer layers, basal to the inner layers and lateral to the side layers. This is important because different functions are performed on different sides of a cell.
*Dlg3: tumor suppressor found in mammals. If this gene is mutated, it causes mental retardation. Dlg 3 stands for Discs large homolog 3, neuroendocrine DLG or synapse-associated protein 102. It is localized on the X chromosome.
*Tight junctions: junctions composed of membrane proteins that hold neighboring cells together and thus also stabilize the cell walls. Tight junctions close the gaps between cells and form a diffusion barrier. Intercellular exchange is possible between the proteins themselves.
* Spemann/Mangold organizer: a structure in the embryo during gastrulation that organizes the development of all the other cells, including neuronal structures.