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FER-1/Dysferlin promotes cholinergic signaling at the neuromuscular junction in C. elegans and mice.

ABSTRACT: Dysferlin is a member of the evolutionarily conserved ferlin gene family. Mutations in Dysferlin lead to Limb Girdle Muscular Dystrophy 2B (LGMD2B), an inherited, progressive and incurable muscle disorder. However, the molecular mechanisms underlying disease pathogenesis are not fully understood. We found that both loss-of-function mutations and muscle-specific overexpression of C. elegans fer-1, the founding member of the Dysferlin gene family, caused defects in muscle cholinergic signaling. To determine if Dysferlin-dependent regulation of cholinergic signaling is evolutionarily conserved, we examined the in vivo physiological properties of skeletal muscle synaptic signaling in a mouse model of Dysferlin-deficiency. In addition to a loss in muscle strength, Dysferlin -/- mice also exhibited a cholinergic deficit manifested by a progressive, frequency-dependent decrement in their compound muscle action potentials following repetitive nerve stimulation, which was observed in another Dysferlin mouse model but not in a Dysferlin-independent mouse model of muscular dystrophy. Oral administration of Pyridostigmine bromide, a clinically used acetylcholinesterase inhibitor (AchE.I) known to increase synaptic efficacy, reversed the action potential defect and restored in vivo muscle strength to Dysferlin -/- mice without altering muscle pathophysiology. Our data demonstrate a previously unappreciated role for Dysferlin in the regulation of cholinergic signaling and suggest that such regulation may play a significant pathophysiological role in LGMD2B disease.

SUBMITTER: Krajacic P

PROVIDER: S-EPMC3828772 | biostudies-literature |

REPOSITORIES: biostudies-literature

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C. elegans dysferlin homolog fer-1 is expressed in muscle, and fer-1 mutations initiate altered gene expression of muscle enriched genes.

Project description:Mutations in the human dysferlin gene cause Limb Girdle Muscular Dystrophy 2B (LGMD2B). The Caenorhabditis elegans dysferlin homolog, fer-1, affects sperms development but is not known to be expressed in or have a functional roles outside of the male germline. Using several approaches, we show that fer-1 mRNA is present in C. elegans muscle cells but is absent from neurons. In mammals, loss of muscle-expressed dysferlin causes transcriptional deregulation of muscle expressed genes. To determine if similar alterations in gene expression are initiated in C. elegans due to loss of muscle-expressed fer-1, we performed whole genome Affymetrix microarray analysis of two loss-of-function fer-1 mutants. Both mutants gave rise to highly similar changes in gene expression and altered the expression of 337 genes. Using multiple analysis methods, we show that this gene set is enriched for genes known to regulate the structure and function of muscle. However, these transcriptional changes do not appear to be in response to gross sarcomeric damage, since genetically sensitized fer-1 mutants exhibit normal thin filament organization. Our data suggest that processes other than sarcomere stability may be affected by loss of fer-1 in C. elegans muscle. Therefore, C. elegans may be an attractive model system in which to explore new muscle-specific functions of the dysferlin protein and gain insights into the molecular pathogenesis of LGMD2B.

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LIN-12/Notch Regulates GABA Signaling at the Caenorhabditis elegans Neuromuscular Junction.

Project description: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.

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Neuromuscular Junction

Project description:NMJ Junction various time points normal C57BL10 LCM mRNA Keywords: other

2005-03-10 | GSE2394 | GEO

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