Molecular and Structural Basis of Olfactory Sensory Neuron Coalescence by Kirrel Receptors

Abstract

Projections from sensory neurons of olfactory systems coalesce into glomeruli in the brain. The Kirrel receptors are believed to homodimerize via their ectodomains and help separate sensory neuron axons into Kirrel2- or Kirrel3-expressing glomeruli. Here we present the crystal structures of homodimeric Kirrel receptors and show that the closely related Kirrel2 and Kirrel3 have evolved specific sets of polar and hydrophobic interactions, respectively, disallowing heterodimerization while preserving homodimerization, likely resulting in proper segregation and coalescence of Kirrel-expressing axons into glomeruli. We show that the dimerization interface at the N-terminal IG domains is necessary and sufficient to create homodimers, and fail to find evidence for a secondary interaction site in Kirrel ectodomains. Furthermore, we show that abolishing dimerization of Kirrel3 in vivo leads to improper formation of glomeruli in the mouse accessory olfactory bulb as observed in Kirrel3-/- animals. Our results provide strong evidence for Kirrel3 homodimerization controlling axonal coalescence.

Shaping the olfactory map: cell type-specific activity patterns guide circuit formation

“…OR-dependent and neural activity-dependent pathways in glomerular segregation converge in the expression pattern of axon sorting molecule. To date, several studies identified multiple activity-dependent axon-sorting molecules that are expressed in OSNs (St John et al, 2002;Cutforth et al, 2003;Kaneko-Goto et al, 2008;Williams et al, 2011;Ihara et al, 2016;Mountoufaris et al, 2017;Vaddadi et al, 2019;Wang et al, 2021;Martinez et al, 2023). The exact number of molecules implicated in this process is still unclear, but a handful of transmembrane proteins are thought to be involved.…”