Adhesion molecules in establishing retinal circuitry

Abstract

The formation of neural circuits requires molecular mechanisms to confer cell identity, to establish appropriate dendritic arbors, and to space cell bodies within the groups of homotypic neurons. Recent work in a variety of organisms has implicated cell adhesion molecules in these processes. The DSCAMs in particular have functions including cell identity and self-avoidance through repulsion in Drosophila, differential adhesion and synaptic pairing in chick retina, and the masking of adhesion within specific cell types in the mouse retina. These differences in molecular function between different organisms, and potentially different cell types within a single tissue, emphasize how seemingly subtle distinctions may be important for deciphering this molecular adhesion code.

Figure 1. Retinal Architecture

The retina is organized in three nuclear laminae and two synaptic laminae. The outer nuclear layer (ONL) is composed of rod and cone photoreceptors (1). The inner nuclear layer (INL) is composed of bipolar cells (2), horizontal cells (3), Mueller glia and amacrine cells (4). The retinal ganglion cell layer (RGL) is composed of amacrine cells and retinal ganglion cells (5). The outer plexiform layer (OPL) contains the synapses between photoreceptors and horizontal and bipolar cells. The inner plexiform layer (IPL) contains the synapses between amacrine, bipolar cells and retinal ganglion cells. The inner plexiform layer can be broadly divided into an ON portion, proximal to the RGL, and an OFF portion, proximal to the INL, or into five synaptic bands (S1–S5). The image is a mature mouse retina cut in cross-section (6 µm) and stained with hematoxyln and Eosin (H&E)

Figure 2. Mosaic patterning, tiling and intermingling

A, Cartoon of a horizontal section (wholemount) of retina. The soma of various cell types, represented by colored circles, are spread across the tissue. B, The cells of a particular cell subtype are non-randomly distributed such that cells of the same type are excluded from a zone around other cells of the same type (the “Exclusion zone”). C, Neurite self-avoidance prevents the neurites of a given cell from crossing other neurites of the same cell (isoneuronal self-avoidance) or neurites of the same cell type (heteroneuronal self-avoidance and tiling). D, Neurite intermingling occurs when the cell bodies of cells of the same type are organized in a mosaic pattern, but the neurites overlap within this population (intermingling).

Figure 3. Intermingled processes of amacrine cell types in the mouse retina

A, B, Examples of bNOS-positive amacrine cells (A), identified using an antibody to bNOS, and dopaminergic amacrine cells (DA), identified with an antibody to tyrosine hydroxylase (B). The neurites of both cell types overlap extensively with the neurites of neighboring cells of the same type, following the pattern shown in Figure 2D, but the intermingled mosaics are independent of one another. Both images are from wild-type, adult mouse retinas and are confocal Z-series projections through the inner plexiform and inner nuclear layers of the wholemount retinas. The scale bar in (B) is equivalent to 193.75 µm.

Figure 4. Mosaic patterning in mouse horizontal and dopaminergic amacrine cells

A, Mouse horizontal cells undergo a stage during which cells are in tiled mosaics. B, By P7 the transient tiled neurites have given way to intermingled neurites. C, At P6 mouse dopaminergic amacrine (DA) cell bodies are spaced in a mosaic pattern in both the wild type and Dscam^−/− (C) retina. The neurites of DA cells are beginning to fasciculate in the Dscam^−/− retina at P6, but remain indifferent to each other in the wild type retina. D, By P10 DA neurites are heavily fasciculated in the Dscam^−/− retina and mosaic spacing of soma is lost.