Fig. 10

Human SPT^HSAN-1 mutations lead to Dscam aggregation and mislocalization. a–d MB axonal morphology in Drosophila ubiquitously expressing (Act5c-Gal4) Spt-I^WT (a) or the mutations Spt-I^C129W(b), Spt-I^C129Y (c), and Spt-I^V140D (d) homologous to human HSAN-1 mutations. MB show axonal morphology defects in HSAN-1 associated mutations (b–d). e–l MB-specific overexpression (OK107-Gal4) of Spt-I mutant constructs with Dscam[TM1]::GFP shows formation of aggregates (arrowheads (j–l)) and also axonal mislocalization (h, arrow). Green: Dscam[TM1]::GFP, Red: FasII, Blue: N-Cad. Scale Bar: 25 μm. m Percentage of MB showing axonal morphology defects in the background of expression of various human SPT mutations. n Percentage of MB showing aggregation and mislocalization of Dscam[TM1]::GFP in the background of expression of various human SPT mutations. Numbers on the bars represent number of MB analyzed. o Model for the role of sphingolipids in the segregation of Dendritic vs. axonal proteins. Sphingolipids regulate segregation of Dendritic (Dscam[TM1] (green)) and axonal (Dscam[TM2]/FasII (blue)) proteins by separating them into vesicles with low (no boundary) or high level (black boundary) of sphingolipids, respectively. These vesicles are then specifically targeted to either dendrites or axons. Cis-membrane interactions between Dscam[TM1] and axonal proteins can define the axo-dendritic boundary during the development. On the other hand, transmembrane homophilic repulsion between Dscam[TM2] isoforms is important for the proper development of axonal morphology