Cell-Surface Proteomic Profiling in the Fly Brain Uncovers Wiring Regulators

Area of Science:

• Neuroscience
• Molecular Biology
• Proteomics

Background:

• Cell-surface interactions are crucial for multicellular organism development and tissue organization.
• Understanding these interactions is key to deciphering neural circuit assembly and brain wiring.

Purpose of the Study:

• To develop a novel method for spatiotemporally resolved cell-surface proteome profiling in intact tissues.
• To identify novel regulators of neural circuit assembly using this proteomic approach.

Main Methods:

• Developed a cell-type-specific, spatiotemporally resolved approach for in situ cell-surface proteome profiling.
• Applied quantitative proteomic profiling to Drosophila olfactory projection neurons (PNs) during development.
• Conducted a proteome-instructed in vivo screen to identify molecules regulating neural circuit assembly.

Main Results:

• Identified global downregulation of wiring molecules and upregulation of synaptic molecules during the transition from developing to mature PNs.
• Discovered 20 cell-surface molecules, many from conserved families, that regulate neural circuit assembly.
• Found that lipoprotein receptor LRP1 cell-autonomously controls PN dendrite targeting.

Conclusions:

• The developed in situ cell-surface proteomic profiling method is powerful for discovering regulators of brain wiring.
• Lipoprotein receptor LRP1 plays a critical role in forming precise neural maps by controlling dendrite targeting.
• This study provides new insights into the molecular mechanisms governing neural development and organization.