Abstract
Different types of neurons in the retina are organized vertically into layers and horizontally in a mosaic pattern that helps ensure proper neural network formation and information processing throughout the visual field. The vertebrate Dscams (DSCAM and DSCAML1) are cell adhesion molecules that support the development of this organization by promoting self-avoidance at the level of cell types, promoting normal developmental cell death, and directing vertical neurite stratification. To understand the molecular interactions required for these activities, we tested the functional significance of the interaction between the C-terminus of the Dscams and multi-PDZ domain-containing scaffolding proteins in mouse. We hypothesized that this PDZ-interacting domain would mediate a subset of the Dscams' functions. Instead, we found that in the absence of these interactions, some cell types developed almost normally, while others resembled complete loss of function. Thus, we show differential dependence on this domain for Dscams' functions in different cell types.
Highlights
The vertebrate retina provides an advantageous model to study how specific neuronal cell types organize themselves during development to form functional circuits
To assess the functional relevance of Down syndrome cell adhesion molecule (DSCAM)’s PDZ-binding motif, we generated a targeted allele of Dscam, in which the sequence encoding the C-terminal 10 amino acids was replaced with sequence encoding a Myc epitope tag (DscamDC, see Figure 1A and Materials and methods)
Deletion of these final 10 amino acids disrupts the canonical binding to the hydrophobic pocket of PDZ domains (Doyle et al, 1996), and this DSCAM-DC mutation markedly reduced MAGI-3 association in co-immunoprecipitation experiments with the DSCAM intracellular domain (ICD) when co-transfected in HEK293T cells (Figure 1B)
Summary
The vertebrate retina provides an advantageous model to study how specific neuronal cell types organize themselves during development to form functional circuits. The ~100 neuronal cell types of the retina vertically organize into layers, with light-transducing photoreceptors in the outermost cellular layer (ONL, or outer nuclear layer) and retinal ganglion cells (RGCs) – responsible for the sole output from the retina – in the innermost layer (RGL, or retinal ganglion cell layer). Many cell types are horizontally spaced in a mosaic pattern, such that there is a low probability of finding two neurons of the same subtype (i.e., homotypic) in close proximity This pattern ensures that the information processing provided by each subtype is distributed across the retina (Masland, 2012)
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