Affinity requirements for control of synaptic targeting and neuronal cell survival by heterophilic IgSF cell adhesion molecules
Shuwa Xu,
Alina P. Sergeeva,
Phinikoula S. Katsamba,
Seetha Mannepalli,
Fabiana Bahna,
Jude Bimela,
S. Lawrence Zipursky,
Lawrence Shapiro,
Barry Honig,
Kai Zinn
Affiliations
Shuwa Xu
California Institute of Technology, Division of Biology and Biological Engineering, Pasadena, CA 91125, USA; Corresponding author
Alina P. Sergeeva
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA
Phinikoula S. Katsamba
Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
Seetha Mannepalli
Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
Fabiana Bahna
Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
Jude Bimela
Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA
S. Lawrence Zipursky
Department of Biological Chemistry, HHMI, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Lawrence Shapiro
Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
Barry Honig
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA
Kai Zinn
California Institute of Technology, Division of Biology and Biological Engineering, Pasadena, CA 91125, USA; Corresponding author
Summary: 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.
