Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA; Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior, The University of Chicago, Chicago, IL 60637, USA.
The Neuro-Montreal Neurological Institute and Hospital, McGill University, Montréal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4, Canada.
Cell Rep. 2021 Nov 2;37(5):109940. doi: 10.1016/j.celrep.2021.109940.
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.
嗅觉系统的感觉神经元投射到大脑中的神经球中。人们认为 Kirrel 受体通过其细胞外结构域同源二聚化，并帮助将感觉神经元轴突分离到表达 Kirrel2 或 Kirrel3 的神经球中。在这里，我们展示了同源二聚体 Kirrel 受体的晶体结构，并表明密切相关的 Kirrel2 和 Kirrel3 分别进化出了特定的极性和疏水性相互作用集，从而阻止异源二聚化，同时保留同源二聚化，可能导致表达 Kirrel 的轴突正确分离并融合到神经球中。我们表明，N 端免疫球蛋白 (IG) 结构域的二聚化界面是形成同源二聚体所必需且充分的，并且未能在 Kirrel 细胞外结构域中找到第二个相互作用位点的证据。此外，我们表明，在体内消除 Kirrel3 的二聚化会导致小鼠副嗅球中神经球的异常形成，正如在 Kirrel3 动物中观察到的那样。我们的结果为 Kirrel3 同源二聚化控制轴突融合提供了证据。
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