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Published April 5, 2022 | Supplemental Material + Accepted Version + Submitted + Published
Journal Article Open

Affinity requirements for control of synaptic targeting and neuronal cell survival by heterophilic IgSF cell adhesion molecules

Abstract

Neurons in the developing brain express many different cell adhesion molecules (CAMs) on their surfaces. CAM-binding affinities can vary by more than 200-fold, but the significance of these variations is unknown. Interactions between the immunoglobulin superfamily CAM DIP-α and its binding partners, Dpr10 and Dpr6, control synaptic targeting and survival of Drosophila optic lobe neurons. We design mutations that systematically change interaction affinity and analyze function in vivo. Reducing affinity causes loss-of-function phenotypes whose severity scales with the magnitude of the change. Synaptic targeting is more sensitive to affinity reduction than is cell survival. Increasing affinity rescues neurons that would normally be culled by apoptosis. By manipulating CAM expression together with affinity, we show that the key parameter controlling circuit assembly is surface avidity, which is the strength of adherence between cell surfaces. We conclude that CAM binding affinities and expression levels are finely tuned for function during development.

Additional Information

© 2022 The Authors. Under a Creative Commons license - Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). Received 30 April 2021, Revised 1 February 2022, Accepted 14 March 2022, Available online 5 April 2022, Version of Record 5 April 2022. We thank the Richard Mann Lab for general discussions. Confocal imaging was completed in the Caltech Biological Imaging Facility. This work was supported by NIH grants R37NS028182 and RO1NS096509 (K.Z.) and NSF grant MCB-1914542 (B.H.). Author contributions. S.X., K.Z., and S.L.Z. conceived the project and wrote the majority of the paper. A.P.S., L.S., and B.H. wrote the section on mutant design and edited the remainder of the paper. S.X. and K.Z. designed the experiments. S.X. conducted the in vivo experiments and analyzed data. A.P.S., L.S., and B. H. designed the protein mutations and analyzed in vitro data. P.S.K. performed and analyzed surface plasmon resonance (SPR) experiments, and S.M., F.B., and J.B. produced and purified proteins. The authors declare no competing interests. Data and code availability: This paper does not report original code. Data reported in this paper will be shared by the corresponding authors upon request. Any additional information required to reanalyze the data reported in this paper is available from the corresponding authors upon request.

Attached Files

Published - 1-s2.0-S2211124722003667-main.pdf

Accepted Version - nihms-1795984.pdf

Submitted - 2021.02.16.431482v1.full.pdf

Supplemental Material - 1-s2.0-S2211124722003667-mmc1.pdf

Supplemental Material - 1-s2.0-S2211124722003667-mmc2.xlsx

Supplemental Material - 1-s2.0-S2211124722003667-mmc3.xlsx

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Additional details

Created:
August 20, 2023
Modified:
December 22, 2023