Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina

Abstract

The retina is a laminated structure made up of several different cellular subtypes, interconnected according to a precise architecture that is vital for proper visual perception. Matsuoka et al. shed new light on the molecular mechanisms governing the development of these circuits. Transmembrane molecules — typically most active as repulsive signals during axonal guidance — exhibit specific expression patterns within the retina that promote appropriate connectivity between cell types. Mutant mice lacking specific isoforms of these semaphorin or plexin molecular families display significant defects in retinal circuitry. Thus, repulsive cues present on the neuronal processes themselves drive proper wiring between lamina within the retina. The retina is a laminated structure made up of several different cellular subtypes that assemble precise connections between them. This study sheds new light on the molecular mechanisms governing the development of these specific circuits. Transmembrane molecules typically most active as repulsive signals during axonal guidance exhibit specific expression patterns within the retina, allowing for the connectivity between cell types to occur properly. Mutant mice lacking specific isoforms of these semaphorin or plexin molecular families displayed significant defects in the retinal circuitry. Thus, repulsive cues present on the neuronal processes themselves drive proper wiring between lamina within the retina. 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)1,2,3, 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 for 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.