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Handara, G. ; Kröger, S.*

Alternative splicing and the intracellular domain mediate TM-agrin's ability to differentially regulate the density of excitatory and inhibitory synapse-like specializations in developing CNS neurons.

Neuroscience 419, 60-71 (2019)
Postprint DOI PMC
Open Access Green
Agrin is a multi-domain protein best known for its essential function during formation of the neuromuscular junction. Alternative mRNA splicing at sites named y and z in the C-terminal part of agrin regulates its interaction with a receptor complex consisting of the agrin-binding low-density lipoprotein receptor-related protein 4 (Lrp4) and the muscle-specific kinase (MuSK). Isoforms with inserts at both splice sites bind to Lrp4, activate MuSK and are synaptogenic at the neuromuscular junction. Agrin is also expressed as a transmembrane protein in the central nervous system (CNS) but its function during interneuronal synapse formation is unclear. Recently we demonstrated that transfection of a full-length cDNA coding for transmembrane agrin (TM-agrin) in cultured embryonic cortical neurons induced an Lrp4-dependent but MuSK-independent increase in dendritic glutamatergic synapses and an Lrp4- and MuSK-independent reduction of inhibitory synapses. Here we show that presynaptic specializations were similarly affected by TM-agrin overexpression. In addition, we mapped the regions within TM-agrin responsible for TM-agrin's effects on dendritic aggregates of synapse-associated proteins. We show that the presence of a four amino acid insert at splice site y is essential for the increase in the density of puncta containing the postsynaptic density protein 95 kDa. This effect was independent of splice site z. The reduction of the gephyrin puncta density was independent of the entire extracellular part of TM-agrin but required a highly conserved serine residue in the intracellular domain of TM-agrin. These results provide further evidence for a function of TM-agrin during CNS synaptogenesis and demonstrate that different domains and alternative splicing of TM-agrin differentially affect excitatory and inhibitory synapse formation in cultured embryonic CNS neurons.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Synaptogenesis ; Vgat ; Vglut1 ; Psd-95 ; Gaba(a) Receptor ; Gephyrin; Neuromuscular-junction Formation; Hippocampal-neurons; Gaba(a) Receptors; Binding Site; Phosphorylation; Muscle; Mechanisms; Isoforms; Requires; Lrp4
ISSN (print) / ISBN 0306-4522
e-ISSN 1873-7544
Zeitschrift Neuroscience
Quellenangaben Band: 419, Heft: , Seiten: 60-71 Artikelnummer: , Supplement: ,
Verlag International Brain Research Organization, Elsevier
Verlagsort The Boulevard, Langford Lane, Kidlington, Oxford Ox5 1gb, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Stem Cell Research (ISF)