Deletion of smn-1, the Caenorhabditis elegans ortholog of the spinal muscular atrophy gene, results in locomotor dysfunction and reduced lifespan.

MRC Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
Human Molecular Genetics (Impact Factor: 7.69). 11/2008; 18(1):97-104. DOI: 10.1093/hmg/ddn320
Source: PubMed

ABSTRACT Spinal muscular atrophy is the most common genetic cause of infant mortality and is characterized by degeneration of lower motor neurons leading to muscle wasting. The causative gene has been identified as survival motor neuron (SMN). The invertebrate model organism Caenorhabditis elegans contains smn-1, the ortholog of human SMN. Caenorhabditis elegans smn-1 is expressed in various tissues including the nervous system and body wall muscle, and knockdown of smn-1 by RNA interference is embryonic lethal. Here we show that the smn-1(ok355) deletion, which removes most of smn-1 including the translation start site, produces a pleiotropic phenotype including late larval arrest, reduced lifespan, sterility as well as impaired locomotion and pharyngeal activity. Mutant nematodes develop to late larval stages due to maternal contribution of the smn-1 gene product that allows to study SMN-1 functions beyond embryogenesis. Neuronal, but not muscle-directed, expression of smn-1 partially rescues the smn-1(ok355) phenotype. Thus, the deletion mutant smn-1(ok355) provides a useful platform for functional analysis of an invertebrate ortholog of the human SMN protein.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases share pathogenic mechanisms at the cellular level including protein misfolding, excitotoxicity and altered RNA homeostasis among others. Recent advances have shown that the genetic causes underlying these pathologies overlap, hinting at the existence of a genetic network for neurodegeneration. This is perhaps best illustrated by the recent discoveries of causative mutations for amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). Once thought to be distinct entities, it is now recognized that these diseases exist along a genetic spectrum. With this wealth of discoveries comes the need to develop new genetic models of ALS and FTD to investigate not only pathogenic mechanisms linked to causative mutations, but to uncover potential genetic interactions that may point to new therapeutic targets. Given the conservation of many disease genes across evolution, Caenorhabditis elegans is an ideal system to investigate genetic interactions amongst these genes. Here we review the use of C. elegans to model ALS and investigate a putative genetic network for ALS/FTD that may extend to other neurological disorders.
    Frontiers in Genetics 01/2014; 5:85.
  • [Show abstract] [Hide abstract]
    ABSTRACT: In biology, homeostasis refers to how cells maintain appropriate levels of activity. This concept underlies a balancing act in the nervous system. Synapses require flexibility (i.e. plasticity) to adjust to environmental challenges. Yet there must also exist regulatory mechanisms that constrain activity within appropriate physiological ranges. An abundance of evidence suggests that homeostatic regulation is critical in this regard. In recent years, important progress has been made towards identifying molecules and signaling processes required for homeostatic forms of neuroplasticity. The Drosophila melanogaster third instar larval neuromuscular junction (NMJ) has been an important experimental system in this effort. Drosophila neuroscientists combine genetics, pharmacology, electrophysiology, imaging, and a variety of molecular techniques to understand how homeostatic signaling mechanisms take shape at the synapse. At the NMJ, homeostatic signaling mechanisms couple retrograde (muscle-to-nerve) signaling with changes in presynaptic calcium influx, changes in the dynamics of the readily releasable vesicle pool, and ultimately, changes in presynaptic neurotransmitter release. Roles in these processes have been demonstrated for several molecules and signaling systems discussed here. This review focuses primarily on electrophysiological studies or data. In particular, attention is devoted to understanding what happens when NMJ function is challenged (usually through glutamate receptor inhibition) and the resulting homeostatic responses. A significant area of study not covered in this review, for the sake of simplicity, is the homeostatic control of synapse growth, which naturally, could also impinge upon synapse function in myriad ways.
    Neuropharmacology 06/2013; · 4.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The determining factor of spinal muscular atrophy (SMA), the most common motor neuron degenerative disease of childhood, is the survival motor neuron (SMN) protein. SMN and its Gemin associates form a complex that is indispensible for the biogenesis of small nuclear ribonucleoproteins (snRNPs), which constitute the building blocks of spliceosomes. It is as yet unclear whether a decreased capacity of SMN in snRNP assembly, and, hence, transcriptome abnormalities, account for the specific neuromuscular phenotype in SMA. Across metazoa, the SMN-Gemins complex concentrates in multiple nuclear gems that frequently neighbour or overlap Cajal bodies. The number of gems has long been known to be a faithful indicator of SMN levels, which are linked to SMA severity. Intriguingly, a flurry of recent studies have revealed that depletion of this nuclear structure is also a signature feature of amyotrophic lateral sclerosis (ALS), the most common adult-onset motor neuron disease. This review discusses such a surprising crossover in addition to highlighting the most recent work on the intricate world of spliceosome building, which seems to be at the heart of motor neuron physiology and survival.
    CNS Neuroscience & Therapeutics 03/2014; · 4.46 Impact Factor

Full-text (2 Sources)

Available from
May 31, 2014