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Published May 14, 2019 | Supplemental Material + Submitted + Published
Journal Article Open

Family of neural wiring receptors in bilaterians defined by phylogenetic, biochemical, and structural evidence


The evolution of complex nervous systems was accompanied by the expansion of numerous protein families, including cell-adhesion molecules, surface receptors, and their ligands. These proteins mediate axonal guidance, synapse targeting, and other neuronal wiring-related functions. Recently, 32 interacting cell surface proteins belonging to two newly defined families of the Ig superfamily (IgSF) in fruit flies were discovered to label different subsets of neurons in the brain and ventral nerve cord. They have been shown to be involved in synaptic targeting and morphogenesis, retrograde signaling, and neuronal survival. Here, we show that these proteins, Dprs and DIPs, are members of a widely distributed family of two- and three-Ig domain molecules with neuronal wiring functions, which we refer to as Wirins. Beginning from a single ancestral Wirin gene in the last common ancestor of Bilateria, numerous gene duplications produced the heterophilic Dprs and DIPs in protostomes, along with two other subfamilies that diversified independently across protostome phyla. In deuterostomes, the ancestral Wirin evolved into the IgLON subfamily of neuronal receptors. We show that IgLONs interact with each other and that their complexes can be broken by mutations designed using homology models based on Dpr and DIP structures. The nematode orthologs ZIG-8 and RIG-5 also form heterophilic and homophilic complexes, and crystal structures reveal numerous apparently ancestral features shared with Dpr-DIP complexes. The evolutionary, biochemical, and structural relationships we demonstrate here provide insights into neural development and the rise of the metazoan nervous system.

Additional Information

© 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Edited by Rachelle Gaudet, Harvard University, Cambridge, MA, and accepted by Editorial Board Member Jeremy Nathans April 8, 2019 (received for review November 5, 2018). We thank Yeonhee J. Park and Elana Baltrusaitis for technical help and Paschalis Kratsios and J.W.T.'s laboratory for discussions and guidance. This work was supported in part by NIH Grants R01 NS097161 (to E.Ö.), R01 GM121931 (to J.W.T.), R37 NS028182 (to K.Z.), and R01 NS096509 (to K.Z.) and a Klingenstein-Simons Fellowship Award in the Neurosciences (to E.Ö.). Use of the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory is supported by the US Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under Contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the NIH, National Institute of General Medical Sciences (NIGMS) (including Grant P41GM103393). This work is also based upon research conducted at the Northeastern Collaborative Access Team beamlines funded by NIGMS from the NIH (Grant P30 GM124165) at the Advanced Photon Source, a US DOE Office of Science user facility operated by the Argonne National Laboratory under Contract DE-AC02-06CH11357. The Pilatus 6M detector on 24-ID-C beamline is funded by NIH Office of Research Infrastructure High-End Instrumentation Grant S10 RR029205. Author contributions: S.C., Y.P., J.D.K., M.J., K.Z., J.W.T., and E.Ö. designed research; S.C., Y.P., J.D.K., and M.J. performed research; S.C., Y.P., J.D.K., K.Z., J.W.T., and E.Ö. analyzed data; and S.C., Y.P., K.Z., J.W.T., and E.Ö. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. R.G. is a guest editor invited by the Editorial Board. Data deposition: The atomic coordinates and structure factors have been deposited in the Protein Data Bank, www.wwpdb.org (PDB ID codes 6ON6, 6ON9, and 6ONB). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1818631116/-/DCSupplemental.

Attached Files

Published - 9837.full.pdf

Submitted - 462036.full.pdf

Supplemental Material - pnas.1818631116.sapp.pdf

Supplemental Material - pnas.1818631116.sd01.txt

Supplemental Material - pnas.1818631116.sd02.txt

Supplemental Material - pnas.1818631116.sd03.txt

Supplemental Material - pnas.1818631116.sd04.txt

Supplemental Material - pnas.1818631116.sd05.txt

Supplemental Material - pnas.1818631116.sd06.txt


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August 22, 2023
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