Control of Axonal Wrapping

In both vertebrates and invertebrates, glial cells wrap axonal processes to ensure electrical conductance. In humans, disruption of the myelin sheath is linked to several severe diseases. We are using Drosophila as a model to identify genes underlying late differentiation of the peripheral glial cells.

In both vertebrates and invertebrates, glial cells wrap axonal processes to ensure electrical conductance. In humans, disruption of the myelin sheath is linked to several severe diseases. Using Drosophila as a model we identify genes underlying late differentiation of the peripheral glial cells. For this, we are using genetic screens and as well as RNAseq experiments to select the relevant candidates. Subsequently, RNAi experiments, CRISPR mediated mutagenesis is used to silence the respective gene function specifically in wrapping glia. We utilize confocal microscopes and electron microscopic studies to determine the respective cellular phenotypes. We already found that Crooked neck (Crn), the Drosophila homologue of the yeast Clf1p splicing factor, is directing glial cell maturation. Within the cytoplasm, Crn interacts with the KH-domain containing RNA binding protein HOW and then translocates to the nucleus. Within the nucleus, the Crn/HOW complex controls glial differentiation by facilitating splicing of specific target genes. By using a GFP-exon trap approach, we identified some of the in vivo target genes, which encode proteins localized in auto-cellular septate junctions (see blood brain barrier). Interestingly, similar mechanisms are also used in the mammalian nervous system to ensure proper myelin formation. Likewise, we identified receptor tyrosin kinases involved in wrapping glia differentiation and again found remarkable similar mechanisms as used during myelination in the mammalian nervous system.  In a recent surevey of all transcriptional regulators we identified many components of the machinery controlling glial differentiation. We are currently focussing on the understanding of neuronal signals ensuring wrapping and the molecules that lead to membrane extension around the axon.