Dscam-Mediated Cell Recognition Regulates Neural Circuit Formation

Abstract

The Dscam family of immunoglobulin cell surface proteins mediates recognition events between neurons that play an essential role in the establishment of neural circuits. The Drosophila Dscam1 locus encodes tens of thousands of cell surface proteins via alternative splicing. These isoforms exhibit exquisite isoform-specific binding in vitro that mediates homophilic repulsion in vivo. These properties provide the molecular basis for self-avoidance, an essential developmental mechanism that allows axonal and dendritic processes to uniformly cover their synaptic fields. In a mechanistically similar fashion, homophilic repulsion mediated by Drosophila Dscam2 prevents processes from the same class of cells from occupying overlapping synaptic fields through a process called tiling. Genetic studies in the mouse visual system support the view that vertebrate DSCAM also promotes both self-avoidance and tiling. By contrast, DSCAM and DSCAM-L promote layerspecific targeting in the chick visual system, presumably through promoting homophilic adhesion. The fly and mouse studies underscore the importance of homophilic repulsion in regulating neural circuit assembly, whereas the chick studies suggest that DSCA Mproteins may mediate a variety of different recognition events during wiring in a context-dependent fashion.

Combinatorial homophilic interaction between γ-protocadherin multimers greatly expands the molecular diversity of cell adhesion

“…This implies that the γ-Pcdh EC1 domain might not directly participate in recognition, which is in agreement with data showing that EC1 from α-Pcdh-A4 has no adhesive properties (19). The requirement for both EC2 and EC3 in γ-Pcdh specificity is reminiscent of interactions between isoforms of Drosophila Dscam, in which homophilic binding specificity is determined by three alternatively spliced Ig domains, all of which must match for interaction to occur (44). Although our experiments focused on two isoforms, it is important to note that all chimeric γ-Pcdhs, including two that had hybrid EC2/EC3 pairs, were able to mediate homophilic cell aggregation comparably with that of WT proteins.…”

Regulatory elements required for the activation and repression of the protocadherin-α gene cluster

“…Studies of the Drosophila Dscam genes have elegantly demonstrated the importance of single-cell diversity of cell-surface proteins in neural circuit assembly (36). In this case, the diversity is generated by stochastic alternative pre-mRNA splicing of an extraordinarily complex pre-mRNA.…”

Role of CCCTC binding factor (CTCF) and cohesin in the generation of single-cell diversity of Protocadherin-α gene expression

“…Specialized genetic mechanisms have evolved to generate this diversity. The Drosophila Dscam1 gene exemplifies one such mechanism, where alternative premRNA splicing generates 19,008 distinct extracellular protein interaction domains (2). This alternative splicing is stochastic; each neuron expresses multiple Dscam1 splice forms, and individual neurons express distinct combinations.…”