Molecular and structural basis of olfactory sensory neuron axon coalescence by Kirrel receptors
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 homodim...
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Published in | Cell reports (Cambridge) Vol. 37; no. 5; p. 109940 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
02.11.2021
Elsevier |
Subjects | |
Online Access | Get full text |
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Summary: | 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 immunoglobulin (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 evidence for Kirrel3 homodimerization controlling axonal coalescence.
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•Mouse Kirrel dimer structures are reported•Kirrel2 and Kirrel3 homodimerize exclusively due to mismatch in interface chemistry•Dimerization specificity determinants are revealed and engineered•Coalescence of vomeronasal axons expressing non-dimerizing Kirrel3 is disrupted
Neuronal surface receptors Kirrels are important for vomeronasal sensory neuron axon identity and coalescence in the brain. Wang et al. report structural and evolutionary origins of exclusive homodimerization of Kirrels. Mice expressing monomeric Kirrel3 show axon coalescence phenotypes, supporting the hypothesis that Kirrel homodimerization underlies axonal coalescence in these neurons. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AC02-06CH11357 USDOE Office of Science (SC), Basic Energy Sciences (BES) E.Ö. and J.F.C. conceptualized the study. J.W. and J.S.P. designed and performed the cell biology and biophysical experiments. C.A.R. and E.Ö. determined crystal structures. Y.P., E.Ö., and J.W.T. performed the phylogenetic analysis. N.V., S.Q., and E.D. were involved in the generation and characterization of genetically modified animals. J.S.P., N.V., E.Ö., and J.F.C. wrote the manuscript. AUTHOR CONTRIBUTIONS |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2021.109940 |