Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina

Abstract

In the vertebrate retina, establishment of precise synaptic connections among distinct retinal neuron cell types is critical for processing visual information and for accurate visual perception. Retinal ganglion cells (RGCs), amacrine cells, and bipolar cells establish stereotypic neurite arborization patterns to form functional neural circuits in the inner plexiform layer (IPL)1–3: a laminar region that is conventionally divided into five major parallel sublaminae1,2. However, the molecular mechanisms governing distinct retinal subtype targeting to specific sublaminae within the IPL remain to be elucidated. Here, we show that the transmembrane semaphorin Sema6A signals through its receptor PlexinA4 (PlexA4) to control lamina-specific neuronal stratification in the mouse retina. Expression analyses demonstrate that Sema6A and PlexA4 proteins are expressed in a complementary fashion in the developing retina: Sema6A in most ON sublaminae and PlexA4 in OFF sublaminae of the IPL. Mice with null mutations in PlexA4 or Sema6A exhibit severe defects in stereotypic lamina-specific neurite arborization of tyrosine hydroxylase (TH)-expressing dopaminergic amacrine cells, intrinsically photosensitive RGCs (ipRGCs), and calbindin-positive cells in the IPL. Sema6A and PlexA4 genetically interact in vivo with respect to the regulation of dopaminergic amacrine cell laminar targeting. Therefore, neuronal targeting to subdivisions of the IPL in the mammalian retina is directed by repulsive transmembrane guidance cues present on neuronal processes.

Semaphorin 6A regulates angiogenesis by modulating VEGF signaling

“…Sema6A-deficient mice are born alive without overt defects and survive to adulthood, but display developmental defects in the nervous system, 15,22,24,[34][35][36][37] some of which normalize after birth in spite of persistent Sema6A-deficiency. 45 Our analysis finds that Sema6A-deficient mice also display vascular developmental defects that were not previously described.…”

“…Sema6A and its receptors plexinA2 and plexinA4 have been extensively characterized for their essential roles in neuronal developmental processes, 22,24,[34][35][36][37] but their roles in vascular development and endothelial cell function remain largely unexplored. Here, we demonstrate that Sema6A contributes to vascular development and to angiogenesis after maturity by modulating VEGFR2 signaling in endothelial cells.…”

“…[22][23][24] Such Sema6A fusion proteins are sequestered in the endoplasmic reticulum and in multiple inclusion bodies (probably lysosomes) and thus the mice are phenotypically Sema6A-null [22][23][24] ; they are born alive and reach adulthood, but display developmental defects in the nervous system, many of which are compensated in the adult mouse. 22,24,[34][35][36][37] No defects in vascular development were previously described.…”

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.…”

So many pieces, one puzzle: cell type specification and visual circuitry in flies and mice

“…Still, the molecular signals leading to precise cell-cell connectivity for most of the known circuits of the mouse retina remain a mystery, and while laminar specificity and synaptic specificity are undoubtedly linked processes at some level, they also display surprising independence. Even in mutants where laminar specificity of a given RGC subtype is severely altered by mutation to semaphorin/ plexin signaling, the dendrites of that RGC still connect with the correct presynaptic partner (Matsuoka et al 2011a). Thus, an additional level of genetic control over retinal wiring must exist to ensure cell-cell synaptic precision independently of laminar depth.…”