Class 5 Transmembrane Semaphorins Control Selective Mammalian Retinal Lamination and Function

Abstract

SUMMARY In the vertebrate retina, neurites from distinct neuronal cell types are constrained within the plexiform layers, allowing for establishment of retinal lamination. However, the mechanisms by which retinal neurites are segregated within the inner or outer plexiform layers are not known. We find that the transmembrane semaphorins Sema5A and Sema5B constrain neurites from multiple retinal neuron subtypes within the inner plexiform layer (IPL). In Sema5A−/−; Sema5B−/− mice, retinal ganglion cells (RGCs), amacrine and bipolar cells exhibit severe defects leading to neurite mistargeting into the outer portions of the retina. These targeting abnormalities are more prominent in the outer (OFF) layers of the IPL and result in functional defects in select RGC response properties. Sema5A and Sema5B inhibit retinal neurite outgrowth through PlexinA1 and PlexinA3 receptors both in vitro and in vivo. These findings define a set of ligands and receptors required for the establishment of inner retinal lamination and function.

Regulation of retinal interneuron subtype identity by theIroquoishomeobox geneIrx6

“…In the Drosophila notum, the Iro complex appears to control axonal projections of medial versus lateral mechanosensory bristles (Grillenzoni et al, 1998). In addition, the Iro complex prevents dorsal photoreceptor axons from misprojecting to the ventral lamina by inhibiting Drosophila Wnt4 (Sato et al, 2006 (Matsuoka et al, 2011). These findings suggest that at least two mechanisms are required for bipolar cell type axonal development: one that defines the division of ON versus OFF boundaries; and one (involving Irx6) that is required for proper positioning within the OFF region.…”

Neuropilin-1 biases dendrite polarization in the retina

“…Yet, we find that Sema3d/f directly influences Xenopus RGC dendrite branching in culture, where presumably additional factors are either absent or present in limited amounts. Recent data in mouse indicate that transmembrane Sema receptors control RGC dendrite growth and targeting (Matsuoka et al, 2011a;Matsuoka et al, 2011b); thus, multiple Sema receptors from distinct families might coordinate the morphogenetic events that underlie proper formation of synaptic connections by RGCs.…”

Semaphorin 5B is a repellent cue for sensory afferents projecting into the developing spinal cord

“…When the Sema5B barrier is removed or reduced, axons enter the grey matter prematurely at the dorsal roots and appear to extend straight into the grey matter. This barrier function of Sema5B is similar to its function in preventing corticofugal fibres from aberrantly projecting into the ventricular zone (Lett et al, 2009) as well as to its function in confining neurites of multiple neuron types to their appropriate lamina in the retina (Matsuoka et al, 2011).…”

“…Neurons (8×10 4 cells) were seeded on top of a confluent layer of stable HEK293 cells expressing either an empty pDisplay vector (control) or an HA-tagged chick Sema5B (chick HA-Sema5B), similar to as previously described (Matsuoka et al, 2011). To select for the growth of nociceptive neurons, culture medium was supplemented with 40 ng/ml 7S nerve growth factor (NGF; Invitrogen), and to select for the growth of proprioceptive neurons the same amount of neurotrophin 3 (NT-3, also known as Ntf3; PeproTech) was used (Chan et al, 2008;Law et al, 2008;Messersmith et al, 1995).…”