Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons
- Howard Hughes Medical Institute, Stanford University, United States
- Columbia University, United States
- Boston Children's Hospital, United States
Abstract
The formation of neural circuits requires extensive interactions of cell-surface proteins to guide axons to their correct target neurons. Trans-cellular interactions of the adhesion G protein-coupled receptor latrophilin-2 (Lphn2) with its partner teneurin-3 instruct the precise assembly of hippocampal networks by reciprocal repulsion. Lphn2 acts as a repulsive receptor in distal CA1 neurons to direct their axons to proximal subiculum, and as a repulsive ligand in proximal subiculum to direct proximal CA1 axons to distal subiculum. It remains unclear if Lphn2-mediated intracellular signaling is required for its role in either context. Here, we show that Lphn2 couples to Gα12/13 in heterologous cells; this coupling is increased by constitutive exposure of the tethered agonist. Specific mutations of Lphn2's tethered agonist region disrupt its G protein coupling and autoproteolytic cleavage, whereas mutating the autoproteolytic cleavage site alone prevents cleavage but preserves a functional tethered agonist. Using an in vivo misexpression assay, we demonstrate that wild-type Lphn2 misdirects proximal CA1 axons to proximal subiculum and that Lphn2 tethered agonist activity is required for its role as a repulsive receptor in axons. By contrast, neither tethered agonist activity nor autoproteolysis was necessary for Lphn2's role as a repulsive ligand in the subiculum target neurons. Thus, tethered agonist activity is required for Lphn2-mediated neural circuit assembly in a context-dependent manner.
Data availability
All materials are available through requests to the corresponding author. All custom code was identical to reported in (Pederick et al., 2021) and can be accessed at https://github.com/dpederick/Reciprocal-repulsions-instruct-the-precise-assembly-of-parallel-hippocampal-networks/tree/1. All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for all Figures.
Article and author information
Author details
Jonathan A Javitch
Funding
National Institutes of Health (T32-MH015144)
- Nicole A Perry-Hauser
National Institutes of Health (R01-NS050835)
- Liqun Luo
National Institutes of Health (R01-MH54137)
- Jonathan A Javitch
Hope for Depression Research Foundation
- Jonathan A Javitch
National Institutes of Health (P30EY012196)
- Zhigang He
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures followed animal care and biosafety guidelines approved by Stanford University's Administrative Panel on Laboratory Animal Care (APLAC 14007) and Administrative Panel on Biosafety (APB-3669-LL120) in accordance with NIH guidelines.
Copyright
© 2023, Pederick et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons
eLife 12:e83529.
https://doi.org/10.7554/eLife.83529
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