Thy-1 is a small membrane glycoprotein and member of the immunoglobulin superfamily of cell adhesion molecules. It is abundantly expressed in many cell types including neurons and is anchored to the outer membrane leaflet via a glycosyl phosphatidylinositol tail. Thy-1 displays a number of interesting properties such as fast lateral diffusion, which allows it to get in and out of membrane nanodomains with different lipid composition. Thy-1 displays a broad expression in different cell types and plays confirmed roles in cell development, adhesion and differentiation. Here, we explored the functions of Thy-1 in neuronal signaling, initiated by extracellular binding of αVβ3 integrin, may strongly dependent on the lipid content of the cell membrane. Also, we assort literature suggesting the association of Thy-1 with specific components of lipid rafts such as sialic acid containing glycosphingolipids, called gangliosides. Furthermore, we argue that Thy-1 positioning in nanodomains may be influenced by gangliosides. We propose that the traditional conception of Thy-1 localization in rafts should be reconsidered and evaluated in detail based on the potential diversity of neuronal nanodomains.

Motor neurons are highly dependent on membrane trafficking, in which the endoplasmic reticulum (ER) and its contact sites with endosomes, confer the ER the role of a long-distance communicator. Atlastin (Atl), a large GTPase located on the ER membrane is required for its function and its tubular structural dynamics. Atl also downregulates, by a yet unknown mechanism, the BMP (Bone Morphogenic Protein) pathway. In humans, Atl mutations are the second more common cause of Hereditary Spastic Paraplegia (HSP), a genetic disease characterized by spasticity of the lower extremities. Here, we explore the molecular basis of Atl-dependent defects on synaptic vesicle (SV) traffic in Drosophila under the hypothesis that those defects are the direct consequence of the Atlastin knock-down and not of the Atl-dependent BMP signaling upregulation. Motor neuronal knockdown of Atl (Atl-KD) leads to an increase in synaptic and satellite bouton number similar to an increase in BMP signaling activity (TKV-CA). Neuronal Atl-KD also associates to a reduction in the boutons of the abundance of the SV markers CSP (Cysteine string protein) and VGLUT (vesicular glutamate transporter) as well as in TKV-CA larvae, both phenotypes are suppressed by decreasing the function of BMP receptor wishful thinking expressing one copy of the mutant receptor (wit /+). Surprisingly, we determined in Atl-KD larvae an increase in the CSP peripheral density and distribution, dependent on synaptic stimulation, that was not replicated in Tkv-CA larvae, suggesting that there could be differences in the mechanisms that underlie the reduction in CSP abundance. Additionally, we determined that Atl-KD associates to an increase in FM 1-43 unload but not in TKV-CA larvae. Moreover, one copy of wit was not able to suppress the FM-143 in Atl-KD larvae (Atl-KD, wit), supporting that BMP signaling does not participate in this phenotype. Together with the stimuli-dependent changes in the SV distribution and dynamics determined in Atl-KD larvae, we measured an increase in Rab11/CSP colocalization, suggesting changes in SV traffic through late recycling endosomes. Together our results suggest a mechanism by which the loss of an ER structuring protein in the motor neuron could, through its role in regulating SV and endosomal trafficking, explain defects in SV accumulation and synaptic dysfunction.