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

Xu, Shuwa and Sergeeva, Alina P. and Katsamba, Phinikoula S. and Mannepalli, Seetha and Bahna, Fabiana and Bimela, Jude and Zipursky, S. Lawrence and Shapiro, Lawrence and Honig, Barry and Zinn, Kai (2022) Affinity requirements for control of synaptic targeting and neuronal cell survival by heterophilic IgSF cell adhesion molecules. Cell Reports, 39 (1). Art. No. 110618. ISSN 2211-1247. PMCID PMC9078203. doi:10.1016/j.celrep.2022.110618. https://resolver.caltech.edu/CaltechAUTHORS:20210218-144331878

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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.

Item Type:

Article

Related URLs:

URL	URL Type	Description
https://doi.org/10.1016/j.celrep.2022.110618	DOI	Article
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9078203	PubMed Central	Article
https://doi.org/10.1101/2021.02.16.431482	DOI	Discussion Paper

ORCID:

Author	ORCID
Xu, Shuwa	0000-0002-0798-487X
Sergeeva, Alina P.	0000-0002-8886-4123
Katsamba, Phinikoula S.	0000-0003-3981-1604
Bimela, Jude	0000-0002-0139-5652
Zipursky, S. Lawrence	0000-0001-5630-7181
Shapiro, Lawrence	0000-0001-9943-8819
Honig, Barry	0000-0002-1835-1031
Zinn, Kai	0000-0002-6706-5605

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.

Funders:

Funding Agency	Grant Number
NIH	R37NS028182
NIH	RO1NS096509
NSF	MCB-1914542

Issue or Number:

PubMed Central ID:

PMC9078203

DOI:

10.1016/j.celrep.2022.110618

Record Number:

CaltechAUTHORS:20210218-144331878

Persistent URL:

https://resolver.caltech.edu/CaltechAUTHORS:20210218-144331878

Official Citation:

Shuwa Xu, Alina P. Sergeeva, Phinikoula S. Katsamba, Seetha Mannepalli, Fabiana Bahna, Jude Bimela, S. Lawrence Zipursky, Lawrence Shapiro, Barry Honig, Kai Zinn, Affinity requirements for control of synaptic targeting and neuronal cell survival by heterophilic IgSF cell adhesion molecules, Cell Reports, Volume 39, Issue 1, 2022, 110618, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2022.110618.

Usage Policy:

No commercial reproduction, distribution, display or performance rights in this work are provided.

ID Code:

108106

Collection:

CaltechAUTHORS

Deposited By:

Tony Diaz

Deposited On:

18 Feb 2021 23:37

Last Modified:

11 May 2022 21:13

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