Brain wiring determinants uncovered by integrating connectomes and transcriptomes

Juyoun Yoo; Mark Dombrovski; Parmis Mirshahidi; Aljoscha Nern; Samuel A LoCascio; S Lawrence Zipursky; Yerbol Z Kurmangaliyev

doi:10.1016/j.cub.2023.08.020

Brain wiring determinants uncovered by integrating connectomes and transcriptomes

Curr Biol. 2023 Sep 25;33(18):3998-4005.e6. doi: 10.1016/j.cub.2023.08.020. Epub 2023 Aug 29.

Authors

Juyoun Yoo¹, Mark Dombrovski², Parmis Mirshahidi², Aljoscha Nern³, Samuel A LoCascio², S Lawrence Zipursky⁴, Yerbol Z Kurmangaliyev⁵

Affiliations

¹ Department of Biological Chemistry, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Neuroscience Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Biological Chemistry, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
⁴ Department of Biological Chemistry, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: lzipursky@mednet.ucla.edu.
⁵ Department of Biological Chemistry, Howard Hughes Medical Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: yerbol@brandeis.edu.

PMID: 37647901
DOI: 10.1016/j.cub.2023.08.020

Abstract

Advances in brain connectomics have demonstrated the extraordinary complexity of neural circuits.¹^,²^,³^,⁴^,⁵ Developing neurons encounter the axons and dendrites of many different neuron types and form synapses with only a subset of them. During circuit assembly, neurons express cell-type-specific repertoires comprising many cell adhesion molecules (CAMs) that can mediate interactions between developing neurites.⁶^,⁷^,⁸ Many CAM families have been shown to contribute to brain wiring in different ways.⁹^,¹⁰ It has been challenging, however, to identify receptor-ligand pairs directly matching neurons with their synaptic targets. Here, we integrated the synapse-level connectome of the neural circuit¹¹^,¹² with the developmental expression patterns⁷ and binding specificities of CAMs⁶^,¹³ on pre- and postsynaptic neurons in the Drosophila visual system. To overcome the complexity of neural circuits, we focus on pairs of genetically related neurons that make differential wiring choices. In the motion detection circuit,¹⁴ closely related subtypes of T4/T5 neurons choose between alternative synaptic targets in adjacent layers of neuropil.¹² This choice correlates with the matching expression in synaptic partners of different receptor-ligand pairs of the Beat and Side families of CAMs. Genetic analysis demonstrated that presynaptic Side-II and postsynaptic Beat-VI restrict synaptic partners to the same layer. Removal of this receptor-ligand pair disrupts layers and leads to inappropriate targeting of presynaptic sites and postsynaptic dendrites. We propose that different Side/Beat receptor-ligand pairs collaborate with other recognition molecules to determine wiring specificities in the fly brain. Combining transcriptomes, connectomes, and protein interactome maps allow unbiased identification of determinants of brain wiring.

Keywords: Drosophila; brain wiring; connectome; interactome; receptor-ligand; synaptic specificity; transcriptome; visual system.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Brain / metabolism
Cell Adhesion Molecules / metabolism
Connectome*
Drosophila / genetics
Drosophila / metabolism
Ligands
Neurons / physiology
Synapses / physiology
Transcriptome

Substances

Ligands
Cell Adhesion Molecules

Grants and funding

P40 OD018537/OD/NIH HHS/United States