A Drosophila Cobblestone Lissencephaly model reveals Dystroglycan is buffered by microRNA-310s via its alternative 3UTR. Halyna R Shcherbata, Andriy S Yatsenko, April K Marrone. MPRG of Gene Expression and Signaling, Max Planck Institute, Goettingen, Germany.

   Dystroglycan (Dg) is a conserved, critical extracellular matrix protein that is responsible for general housekeeping processes relevant to total organism health. We show that in Drosophila the Dg mRNA is subject to alternative 3UTR processing making it to some extent visible to miRNA targeting and consequential degradation, which offers an extra layer of expression precision. This precision of Dg levels is especially important in the nervous system, where misexpressed Dg causes high levels of lethality, deformed brain shape and neuroblast cell cycle defects. ECM-dependent regulation of cell-cycle progression can be mediated by mechanical stress sensors and since Dg is a mechano-signaling transmitter, we propose that Dg is involved in a signal-transduction mechanism through which the extracellular matrix regulates the speed of neuronal stem cell division. Interestingly, levels of Dg per se are critical to coordinate proper formation of the 3D architecture of the developing brain. Dg misexpression affects localization of multiple ECM proteins, resulting in formation of tumor-like structures that outgrow the normal contour of the ECM-defined brain space. This phenotype is similar to the brain cortex abnormalities associated with dystroglycanopathies in humans, implying that Drosophila Dg mutants can serve as a model for cobblestone lissencephaly. We found that misexpression of Dg affects the distribution of major cell adhesion proteins, which affects the ECM composition consequently resulting in abnormal tissue assembly. Since multiple aspects of neuron maturation involve rigorous rearrangements of cell shape and form, and ECM receptors, and particularly Dg is activated by mechanical stress due to cell shape reorganization. After the completion of cell shape rearrangements baseline Dg levels have to be reestablished and our data suggest that the miR-310s are induced in response to higher Dg levels to manage the amount of this ECM receptor.