RRC ID 56224
Author Sorkaç A, DiIorio MA, O'Hern PJ, Baskoylu SN, Graham HK, Hart AC.
Title LIN-12/Notch Regulates GABA Signaling at the Caenorhabditis elegans Neuromuscular Junction.
Journal G3 (Bethesda)
Abstract The role of Notch signaling in cell-fate decisions has been studied extensively; however, this pathway is also active in adult tissues, including the nervous system. Notch signaling modulates a wide range of behaviors and processes of the nervous system in the nematode Caenorhabditis elegans, but there is no evidence for Notch signaling directly altering synaptic strength. Here, we demonstrate Notch-mediated regulation of synaptic activity at the C. elegans neuromuscular junction (NMJ). For this, we used aldicarb, an inhibitor of the enzyme acetylcholinesterase, and assessed paralysis rates of animals with altered Notch signaling. Notch receptors LIN-12 and GLP-1 are required for normal NMJ function; they regulate NMJ activity in an opposing fashion. Complete loss of LIN-12 skews the excitation/inhibition balance at the NMJ toward increased activity, whereas partial loss of GLP-1 has the opposite effect. Specific Notch ligands and co-ligands are also required for proper NMJ function. The role of LIN-12 is independent of cell-fate decisions; manipulation of LIN-12 signaling through RNAi knockdown or overexpression of the co-ligand OSM-11 after development alters NMJ activity. We demonstrate that LIN-12 modulates GABA signaling in this paradigm, as loss of GABA signaling suppresses LIN-12 gain-of-function defects. Further analysis, in vivo and in silico, suggests that LIN-12 may modulate transcription of the GABAB receptor GBB-2 Our findings confirm a non-developmental role for the LIN-12/Notch receptor in regulating synaptic signaling and identify the GABAB receptor GBB-2 as a potential Notch transcriptional target in the C. elegans nervous system.
Volume 8(8)
Pages 2825-2832
Published 2018-7-31
DOI 10.1534/g3.118.200202
PII g3.118.200202
PMID 29950427
PMC PMC6071610
MeSH Aldicarb / pharmacology Animals Caenorhabditis elegans / drug effects Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cholinesterase Inhibitors / pharmacology Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism Mutation Neuromuscular Junction / drug effects Neuromuscular Junction / metabolism* Receptors, Notch / genetics Receptors, Notch / metabolism* Signal Transduction* / drug effects gamma-Aminobutyric Acid / metabolism*
IF 2.63
Times Cited 1
C.elegans tm2256 tm4515 tm1805