Interplay between cell-adhesion molecules governs synaptic wiring of cone photoreceptors

Abstract

Establishment of functional synaptic connections in a selective manner is essential for nervous system operation. In mammalian retinas, rod and cone photoreceptors form selective synaptic connections with different classes of bipolar cells (BCs) to propagate light signals. While there has been progress in elucidating rod wiring, molecular mechanisms used by cones to establish functional synapses with BCs have remained unknown. Using an unbiased proteomic strategy in cone-dominant species, we identified the cell-adhesion molecule ELFN2 to be pivotal for the functional wiring of cones with the ON type of BC. It is selectively expressed in cones and transsynaptically recruits the key neurotransmitter receptor mGluR6 in ON-BCs to enable synaptic transmission. Remarkably, ELFN2 in cone terminals functions in synergy with a related adhesion molecule, ELFN1, and their concerted interplay during development specifies selective wiring and transmission of cone signals. These findings identify a synaptic connectivity mechanism of cones and illustrate how interplay between adhesion molecules and postsynaptic transmitter receptors orchestrates functional synaptic specification in a neural circuit.

Trans-Synaptic Regulation of Metabotropic Glutamate Receptors by Elfn Proteins in Health and Disease

“…The binding of Elfn1 with mGluR6 is proposed to play an essential role in the formation of the synaptic contact, as elimination of either component results in a similar loss of synapses (Cao et al, 2015 ). Furthermore, ELFN2 that directly associates with mGluR6 is pivotal for the functional wiring cones with cone ON bipolar cells (Cao et al, 2020 ). In mouse retinal development, Elfn1 and Elfn2 show distinct developmental expression profiles and synergistically control the functional wiring of cones with cone ON-bipolar cells (Cao et al, 2020 ; Figures 1I,K ).…”

“…Furthermore, ELFN2 that directly associates with mGluR6 is pivotal for the functional wiring cones with cone ON bipolar cells (Cao et al, 2020 ). In mouse retinal development, Elfn1 and Elfn2 show distinct developmental expression profiles and synergistically control the functional wiring of cones with cone ON-bipolar cells (Cao et al, 2020 ; Figures 1I,K ). In the combination of studies on pyramidal-to-OLM synapses and on retinal photoreceptor-bipolar cell synapses, Elfn proteins are necessary for both synapse formation and functional specification and can be mGluR trans-binding partners on both the presynaptic and postsynaptic sides.…”

“…Their results indicate that ELFN1 selectively binds all group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8), but not the other mGluR species ( Figure 1B ; Dunn et al, 2018 ). Elfn2 was also shown to bind group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8; Dunn et al, 2019b ; Cao et al, 2020 ).…”

“…Flrt proteins are leucine-rich repeat (LRR) and fibronectin type III domain-containing transmembrane proteins (LRRFn) and are similar to the extracellular LRR fibronectin domain-containing family of proteins (Elfn1 and Elfn2) in terms of domain organization ( Figure 1A ; Dolan et al, 2007 ). Elfn proteins have been shown to trans-interact with the glutamate (class C) family of GPCRs (Tomioka et al, 2014 ; Cao et al, 2015 , 2020 ; Dunn et al, 2018 , 2019b ) that are distantly located from the adhesion (class B) family in the human GPCR molecular phylogeny ( Figure 1B ; Fredriksson et al, 2003 ). Therefore, the trans-regulation of GPCRs by Flrt and Elfn family proteins is thought to occur independently during evolution.…”

“…(J) Elfn1 bridges the functional interaction between the glutamate release-directing Ca V 1.4 channel and glutamate-sensing mGluR6 (Cao et al, 2015 ). (K) Cone cells express Elfn1 during early synaptogenesis and switch to ELFN2 to support synaptic signaling in mature retinas (Cao et al, 2020 ).…”