Alternative Splicing of Drosophila Dscam Generates Axon Guidance Receptors that Exhibit Isoform-Specific Homophilic Binding

Abstract

Dscam is an immunoglobulin (Ig) superfamily protein required for the formation of neuronal connections in Drosophila. Through alternative splicing, Dscam potentially gives rise to 19,008 different extracellular domains linked to one of two alternative transmembrane segments, resulting in 38,016 isoforms. All isoforms share the same domain structure but contain variable amino acid sequences within three Ig domains in the extracellular region. We demonstrate that different isoforms exhibit different binding specificity. Each isoform binds to itself but does not bind or binds poorly to other isoforms. The amino acid sequences of all three variable Ig domains determine binding specificity. Even closely related isoforms sharing nearly identical amino acid sequences exhibit isoform-specific binding. We propose that this preferential homophilic binding specificity regulates interactions between cells and contributes to the formation of complex patterns of neuronal connections.

Dscam-mediated repulsion controls tiling and self-avoidance

“…And finally, Dscam1 is required for the segregation of sister branches in mushroom body neurons, a process similar to self-avoidance [8]. These observations led to the proposal that Dscam1 promotes homophilic repulsion in vivo [9] [7]. Note that in previous publications we referred to this Dscam paralog as Dscam.…”

“…First, the Dscam1 locus can generate tens of thousands of different recognition molecules through alternative splicing [5] and each neuron appears to express a unique combination of isoforms [6]. Second, each Dscam1 isoform mediates homophilic, but not heterophilic binding with other isoforms and thus, this single gene could generate the diversity required for self-recognition throughout the nervous system [7]. And finally, Dscam1 is required for the segregation of sister branches in mushroom body neurons, a process similar to self-avoidance [8].…”

Neurite arborization and mosaic spacing in the mouse retina require DSCAM

“…In flies, Dscam is alternatively spliced to generate tens of thousands of protein isoforms 6 . The homophilic interaction of DSCAM is highly isoform-specific, and this specificity is determined by the variable immunoglobulin domains 8,22,23 . Therefore, Drosophila neurons use DSCAM for isoneuronal self-avoidance and arborization because each cell recognizes only its own processes, which express the same set of isoforms 8,9,24 .…”

“…7). DSCAM may function similarly in other regions of the mammalian nervous system, and this role may extend to other members of the mammalian Dscam gene family.We have identified a spontaneous mutation in mice that creates a loss-of-function allele of Dscam, the Drosophila homologues of which function in both isoneuronal self-avoidance for dendrite arborization and heteroneuronal self-avoidance for axon tiling [7][8][9][10][11][12] . The recessive mutation arose in the BALB/cByJ genetic background and caused an overt neurological phenotype.…”

Dendritic self-avoidance: protocadherins have it covered

“…cassettes potentially generates 19 008 Dscam1 isoforms that differ in their extracellular domain and are capable of isoform-specific homophilic binding [2,3]. Loss of Dscam1 from single sensory neurons leads to excess overlap of isoneuronal branches, indicating a defect in self-avoidance.…”