Dscam1-Mediated Self-Avoidance Counters Netrin-Dependent Targeting of Dendrites in Drosophila

Abstract

SUMMARY Dendrites and axons show precise targeting and spacing patterns for proper reception and transmission of information in the nervous system. Self-avoidance promotes complete territory coverage and non-overlapping spacing between processes from the same cell [1, 2]. Neurons that lack Drosophila Down syndrome cell adhesion molecule 1 (Dscam1) show aberrant overlap, fasciculation, and accumulation of dendrites and axons, demonstrating a role in self-recognition and repulsion leading to self-avoidance [3–11]. Fasciculation and accumulation of processes suggested that Dscam1 might promote process spacing by counterbalancing developmental signals that otherwise promote self-association [9, 12]. Here we show that Dscam1 functions to counter sensory neuron dendritic targeting signals provided by secreted Netrin-B and Frazzled, a netrin receptor. Loss of Dscam1 function resulted in aberrant dendrite accumulation at a Netrin-B expressing target, whereas concomitant loss of Frazzled prevented accumulation and caused severe deficits in dendritic territory coverage. Netrin misexpression was sufficient to induce ectopic dendritic targeting in a Frazzled-dependent manner, whereas Dscam1 was required to prevent ectopic accumulation, consistent with separable roles for these receptors. Our results suggest that Dscam1-mediated self-avoidance counter extrinsic signals that are required for normal dendritic patterning, but whose action would otherwise favor neurite accumulation. Counterbalancing roles for Dscam1 may be deployed in diverse contexts during neural circuit formation.

DSCAM-mediated control of dendritic and axonal arbor outgrowth enforces tiling and inhibits synaptic plasticity

“…Since Dscam is widely expressed throughout the CNS (75-77), similar perturbations of receptive and projective fields in the brain should be of potential interest for exploring links between mutations in Dscam and autism in humans (78,79). (49,(80)(81)(82)(83)(84), laminar targeting (25,38), and avoidance (22,24,44,45,85,86). In this study, we report that DSCAM acts in mature neurons to actively suppress dendrite growth, a novel mechanism to inhibit plasticity.…”

A Novel Mouse Dscam Mutation Inhibits Localization and Shedding of DSCAM

“…Dscams have been most thoroughly studied in Drosophila, and mediate a similar range of processes as their vertebrate homologues, which lack the extensive alternative splicing observed in Drosophila Dscam1 [21], [22], [23], [24], [25], [26], [27]. Studies of vertebrate Dscams have identified at least three potential functions for these genes that overlap with functions demonstrated for their homologues in Drosophila.…”

The Glide/Gcm fate determinant controls initiation of collective cell migration by regulating Frazzled

“…NetA and NetB have been suggested to act on the embryonic longitudinal glia through Fra (von Hilchen et al, 2010) and both Netrins are reported to act as chemoattractants, even though in one case, only NetB was proposed to mediate dendritic targeting via Fra (Matthews and Grueber, 2011). Clearly, downregulating or overexpressing NetA has no impact on the migrating glial cells of the wing and NetA cannot rescue the NetB phenotype.…”