Neuronal Migration and Lamination in the Vertebrate Retina

Abstract

In the retina, like in most other brain regions, developing neurons are arranged into distinct layers giving the mature tissue its stratified appearance. This process needs to be highly controlled and orchestrated, as neuronal layering defects lead to impaired retinal function. To achieve successful neuronal layering and lamination in the retina and beyond, three main developmental steps need to be executed: First, the correct type of neuron has to be generated at a precise developmental time. Second, as most retinal neurons are born away from the position at which they later function, newborn neurons have to move to their final layer within the developing tissue, a process also termed neuronal lamination. Third, these neurons need to connect to their correct synaptic partners. Here, we discuss neuronal migration and lamination in the vertebrate retina and summarize our knowledge on these aspects of retinal development. We give an overview of how lamination emerges and discuss the different modes of neuronal translocation that occur during retinogenesis and what we know about the cell biological machineries driving them. In addition, retinal mosaics and their importance for correct retinal function are examined. We close by stating the open questions and future directions in this exciting field.

Keywords: connectivity; lamination; mosaics; neuronal migration; retina.

Figure 1

The vertebrate retina has a laminar organization. (A) Sagittal section of a mature zebrafish retina in vivo, showing lamination of cell bodies. The retinal cells are labeled with a combination of membrane-tagged fluorescent proteins that allows the identification of all the major neuronal types. In Cyan, the photoreceptors and bipolar cells under Crx promoter (Crx:gapCFP). In yellow, the horizontal cells, amacrine cells, and displaced amacrine cells under Ptf1a promoter (Ptf1a:Gal4/UAS:gapYFP). In magenta, the retinal ganglion cells under Ath5 promoter (Atoh7:gapRFP). Arrows indicate horizontal cells and displaced-amacrine cells. This image is a courtesy of Jaroslav Icha. The dashed box shows the area depicted by the schematic representation in (B). (B) Schematic representation of a cross-section of the mature retina in zebrafish showing lamination of cell bodies and their neurites. The cell bodies of the retinal cell types are organized into three layers from apical to basal; the outer nuclear layer (ONL), the inner nuclear layer (INL), and the ganglion cell layer (GCL). These three layers are segregated by two plexiform layers enriched with axonal and dendritic processes, namely the outer plexiform layer (OPL) and the inner plexiform layer (IPL). The primary sensory neurons; rod and cone photoreceptors (cyan) are located at the most apical layer (ONL). The interneurons; horizontal cells (yellow), bipolar cells (blue), and amacrine cells (light yellow) are distributed along the apico-basal axis of the INL. The displaced amacrine cells (light yellow) and the output neurons retinal ganglion cells (magenta) occupy the most basal layer (GCL). PR, Photoreceptors; HC, horizontal cells; BC, bipolar cells; AC, amacrine cells; dAC, displaced amacrine cells; RGC, retinal ganglion cells.

Figure 2

Genesis of the neuronal types of the vertebrate retina. (A) Chronological order of neuron birth in the vertebrate retina is depicted based on classical birth dating studies done across many vertebrate species. The first neurons born are the retinal ganglion cells, followed by cone photoreceptors, horizontal cells, amacrine cells, rod photoreceptors, and bipolar cells. Note that birth orders are overlapping and that we did not depict Muller cells in the schematic but they are the latest born cell-type. (B) Model of retinogenesis in the zebrafish embryo. Neuroepithelial progenitors (gray) divide asymmetrically at the apical side and give birth to one neuron either a retinal ganglion cell (magenta) or amacrine cell (light yellow) and one neuronal precursor committed to cone photoreceptor (cyan), horizontal (yellow), or bipolar (blue) cell fate. The committed precursors feature distinct morphology, expression of fate determinants and/or mitotic position. Cone photoreceptor precursors (cyan) show columnar epithelial morphology and divide within the developing photoreceptor layer at the apical surface of the retina. Horizontal cell precursors (yellow) are nonpolar and divide along the apico-basal axis of the INL, whereas bipolar cell precursors (blue) show bipolar morphology and can divide at apical or subapical positions. PR, Photoreceptors; HC, horizontal cells; BC, bipolar cells; AC, amacrine cells; dAC, displaced amacrine cells; RGC, retinal ganglion cells.

Figure 3

Modes of neuronal migration in the CNS. Two main modes of migration have been described in different parts of the nervous system: (A) Radial migration and (B) tangential migration. (A) A prevalent type of radial migration in the cortex is the glial-guided migration. It can be schematically summarized in three steps: (1) neurons born at the apical surface (2) lose their attachments to both the apical and basal surfaces of the tissue, (3) they attach to the radially oriented glial cells, (4) move along them to their target location perpendicular to the surfaces of the tissue and (5) undergo differentiation. (B) Some neurons combine radial migration with tangential migration to reach their target position. Tangentially migrating cells are not attached to the edges of the tissue and most of them form branched leading processes (arrowheads). As an example, tangential migration of interneurons is shown in three steps: (1) migration toward the cortex and move in parallel to the apical and basal surfaces, (2) interneurons subsequently associate with glial cells, (3) undergo radial movement along the glial-cells perpendicular to the apical surface and (4) reach their position and (5) undergo differentiation.

Figure 4

Modes of neuronal migration in the retina. (A,B) Scheme of different retinal ganglion cells (green) translocation modes: (A) somal translocation with basal process and (B) multipolar migration. (A) Retinal ganglion cells inheriting the basal process in zebrafish translocate basally faster than the sister cell. Basal translocation is followed by a period of fine positioning, during which cells lose their apical processes and project axons toward the optic nerve (depicted by arrows). (B) In rare cases in zebrafish, retinal ganglion cells lose their basal process, subsequently detach their apical process, increase their protrusive activity, and move basally in a multipolar migratory mode. The model shown is adapted from Icha et al. (2016) study. (C) Representation of retinal inhibitory neurons migration. Amacrine cells (gray) and the committed horizontal cell precursors (green) migrate to their laminar position via a combination of bipolar somal translocation and multipolar migration. Upon birth, they move away from the apical side using somal translocation. Later, they switch to a multipolar mode of migration and translocate their soma deeper into the INL. Amacrine cells remain at the basal INL positions, while horizontal cells revert their trajectory and migrate back toward the most-apical region of the INL, beneath the photoreceptor layer. On their way to the apical side, the committed horizontal cell precursors undergo mitosis with no positional preference along the INL. This model takes into account results from previous studies in the zebrafish retina (Weber et al., ; Chow et al., ; Icha et al., 2016).

Figure 5

Mosaic assembly of horizontal cells in the vertebrate retina. (A) Schematic representation of a cross-section of the vertebrate retina showing that individual horizontal cells (yellow) are evenly spaced across the retina, a pattern known as retinal mosaics. (B) Schematic view from the surface of the retina in (A) showing that cell bodies and dendrites of horizontal cells of the same type are non-randomly distributed within the horizontal cell layer. Dendritic territories of the homotypic neighboring neurons show little or no overlap. This phenomenon is also referred to as dendritic tiling. The dashed box shows the area depicted in (C). (C) Mosaic of horizontal cells arises by contact-mediated repulsion among these neurons. Horizontal cells of the same type express the same cell-surface molecules (depicted in turquoise). This allows the homotypic neurons to recognize each other and generate contact-dependent repulsion between their dendrites (depicted by red arrows), thereby creating mosaic spacing of horizontal cell soma. This figure takes into account results from previous studies in the vertebrate retina (Wässle and Riemann, ; Scheibe et al., ; Huckfeldt et al., ; Kay et al., 2012).