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ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior.

ABSTRACT: The functional characterization of the GPCR interactome has predominantly focused on intracellular binding partners; however, the recent emergence of transsynaptic GPCR complexes represents an additional dimension to GPCR function that has previously been unaccounted for in drug discovery. Here, we characterize ELFN2 as a novel postsynaptic adhesion molecule with a distinct expression pattern throughout the brain and a selective binding with group III metabotropic glutamate receptors (mGluRs) in trans. Using a transcellular GPCR signaling platform, we report that ELFN2 critically alters group III mGluR secondary messenger signaling by directly altering G protein coupling kinetics and efficacy. Loss of ELFN2 in mice results in the selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission. Elfn2 knockout (Elfn2 KO) mice also feature a range of neuropsychiatric manifestations including seizure susceptibility, hyperactivity, and anxiety/compulsivity, which can be rescued by pharmacological augmentation of group III mGluRs. Thus, we conclude that extracellular transsynaptic scaffolding by ELFN2 in the brain is a cardinal organizational feature of group III mGluRs essential for their signaling properties and brain function.

SUBMITTER: Dunn HA

PROVIDER: S-EPMC6874751 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior.

Dunn Henry A HA Zucca Stefano S Dao Maria M Orlandi Cesare C Martemyanov Kirill A KA

Molecular psychiatry 20190904 12

The functional characterization of the GPCR interactome has predominantly focused on intracellular binding partners; however, the recent emergence of transsynaptic GPCR complexes represents an additional dimension to GPCR function that has previously been unaccounted for in drug discovery. Here, we characterize ELFN2 as a novel postsynaptic adhesion molecule with a distinct expression pattern throughout the brain and a selective binding with group III metabotropic glutamate receptors (mGluRs) in ...[more]

PMID: 31485013

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Project description:Cleft palate results from a mixture of genetic and environmental factors and occurs when the bilateral palatal shelves fail to fuse. The objective of this study was to search for new genes involved in mouse palate formation. Gene expression of murine embryonic palatal tissue was analyzed at the various developmental stages before, during, and after palate fusion using GeneChip? microarrays. Ceacam1 was one of the highly up-regulated genes during and after fusion in palate formation, and this was confirmed by quantitative real-time PCR. Immunohistochemical staining showed that CEACAM1 was expressed at a very low level in palatal epithelium before fusion, but highly expressed in the midline of the palate during and after fusion. To investigate the developmental role of CEACAM1, function-blocking antibody was added to embryonic mouse palate in organ culture. Palatal fusion was inhibited by this function-blocking antibody. To investigate the subsequent developmental role of CEACAM1, we characterized Ceacam1-deficient (Ceacam1-/-) mice. Epithelial cells persisted abnormally at the midline of the embryonic palate even on day E16.0, and palatal fusion was delayed in Ceacam1-/- mice. TGF?3 expression, apoptosis, and cell proliferation in palatal epithelium were not effected in the palate of Ceacam1-/-mice. CEACAM1 expression was down-regulated in Tgfb3-/- palate. However, exogenous TGF?3 did not induce CEACAM1 expression. These results suggest that CEACAM1 has roles in both the initiation of palate formation via epithelial cell adhesion and TGF signaling has some indirect effect on CEACAM1. Global gene expression profiling of palatal processes before, during and after fusion of palatal shelves We used microarray to investigate the gene expression of palatal tissue during palatal development. Palatal processes were microdissected at the stages of palatal development (before, during and after fusion) for RNA extraction and hybridization on Affymetrix microarrays.

Dataset Information

ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior.

Publications

ELFN2 is a postsynaptic cell adhesion molecule with essential roles in controlling group III mGluRs in the brain and neuropsychiatric behavior.

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