L1CAM/Neuroglian controls the axon-axon interactions establishing layered and lobular mushroom body architecture.
Bottom Line: We demonstrate that the Drosophila melanogaster L1CAM homologue Neuroglian mediates adhesion between functionally distinct mushroom body axon populations to enforce and control appropriate projections into distinct axonal layers and lobes essential for olfactory learning and memory.For functional cluster formation, intracellular Ankyrin2 association is sufficient on one side of the trans-axonal complex whereas Moesin association is likely required simultaneously in both interacting axonal populations.Together, our results provide novel mechanistic insights into cell adhesion molecule-mediated axon-axon interactions that enable precise assembly of complex neuronal circuits.
Affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland University of Basel, 4003 Basel, Switzerland.Show MeSH
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Mentions: Phosphorylation of the tyrosine residue within the FIGQY motif negatively regulates the binding of L1 protein family members to Ankyrins (Garver et al., 1997; Tuvia et al., 1997). This effect can be mimicked by specific amino acid substitutions, which alter binding to Ank2 and change the mobility of L1CAM in vitro (Gil et al., 2003) or of Nrg in axons in vivo (Enneking et al., 2013). Similar to nrg14; P[nrg180_ΔFIGQY] mutant animals, a point mutation abolishing the Nrg–Ank2 interaction (YA) failed to rescue MB development (nrg14; P[nrg180_YA]; Fig. 4 G). In contrast, a point mutation inducing a constitutive Nrg–Ank2 interaction by rendering the tyrosine nonphosphorylatable (YF) efficiently restored MB axon projections into the pedunculus and the anterior lobes (nrg14; P[nrg180_YF]; Fig. 4, F and G). Interestingly, in YF mutants we observed minor defects in α lobe tip innervation and a partial fusion of the β lobes from the two brain hemispheres, which indicates that a dynamic regulation of the Nrg–Ank2 interaction is essential for normal lobe morphogenesis (Fig. 4 F; and Fig. S2, A–C). To independently test the requirement of a cytoplasmic Nrg–Ank2 association, we performed genetic interactions assays. The nrg allele nrg305 significantly reduced expression of both Nrg isoforms (Fig. 5 E) and caused MB lobe formation defects in 65% of brain hemispheres but only mildly affected axonal projection into the pedunculus (Fig. 5, A and D). Strikingly, removal of one copy of ank2 (using the ank2- allele ank2518) in hemizygous nrg305 mutant animals resulted in a dramatic enhancement of the phenotype, with 80% of αβ axons now failing to enter the pedunculus (Fig. 5, C and D). Because the ank2518 allele did not impair MB development in heterozygosity (Fig. 5, B and D), these data are consistent with the Nrg–Ank2 interaction contributing to MB axon guidance (Fig. 5 J).
Affiliation: Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland University of Basel, 4003 Basel, Switzerland.