An Attractive Reelin Gradient Establishes Synaptic Lamination in the Vertebrate Visual System

Highlights

• Reelin is required for lamina-specific targeting of RGC axons in the neuropil

• VLDLR and Dab1a transmit Reelin signaling to RGCs

• Reelin is gradually distributed and stabilized by HSPGs in the neuropil

• Chemoattractant Reelin conveys lamina-specific positional information to RGC axons

Summary

A conserved organizational and functional principle of neural networks is the segregation of axon-dendritic synaptic connections into laminae. Here we report that targeting of synaptic laminae by retinal ganglion cell (RGC) arbors in the vertebrate visual system is regulated by a signaling system relying on target-derived Reelin and VLDLR/Dab1a on the projecting neurons. Furthermore, we find that Reelin is distributed as a gradient on the target tissue and stabilized by heparan sulfate proteoglycans (HSPGs) in the extracellular matrix (ECM). Through genetic manipulations, we show that this Reelin gradient is important for laminar targeting and that it is attractive for RGC axons. Finally, we suggest a comprehensive model of synaptic lamina formation in which attractive Reelin counter-balances repulsive Slit1, thereby guiding RGC axons toward single synaptic laminae. We establish a mechanism that may represent a general principle for neural network assembly in vertebrate species and across different brain areas.