Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons.

Autor: Pederick DT; Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States., Perry-Hauser NA; Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, United States.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, United States., Meng H; F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, United States., He Z; F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, United States., Javitch JA; Departments of Psychiatry and Molecular Pharmacology and Therapeutics, Columbia University Vagelos College of Physicians and Surgeons, New York, United States.; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, United States., Luo L; Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States.
Jazyk: angličtina
Zdroj: ELife [Elife] 2023 Mar 20; Vol. 12. Date of Electronic Publication: 2023 Mar 20.
DOI: 10.7554/eLife.83529
Abstrakt: 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 the proximal subiculum, and as a repulsive ligand in the proximal subiculum to direct proximal CA1 axons to the 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 Gα 12/13 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 the 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 were 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.
Competing Interests: DP, NP, HM, ZH, JJ, LL No competing interests declared
(© 2023, Pederick, Perry-Hauser et al.)
Databáze: MEDLINE
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