Briese, M. et al. Deletion of smn-1, the Caenorhabditis elegans ortholog of the spinal muscular atrophy gene, results in locomotor dysfunction and reduced lifespan. Hum. Mol. Genet. 18, 97-104

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: 6.39). 11/2008; 18(1):97-104. DOI: 10.1093/hmg/ddn320
Source: PubMed


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.

Download full-text


Available from: Emma C Burt,
  • Source
    • "This situation must be mimicked in cell and animal models of the disease if meaningful insights are to be made about protein function and disease mechanisms. SMN depletion has been modelled in numerous organisms ranging from yeast and invertebrates to fish, mice, and pigs [6] [7] [8] [9] [10] [11] [12] [13]. Here, we review presentations from the latest UK SMA research conference and discuss how this work fits into the current SMA research picture. "

  • Source
    • "Smn family members were previously shown to regulate small nuclear ribonucleoprotein (snRNP) biogenesis (Fischer et al., 1997), and loss of human SMN1 or SMN2 function causes spinal muscular atrophy (Coovert et al., 1997; Lefebvre et al., 1997). Several studies of Smn in invertebrate model systems have been conducted to help elucidate the mechanisms by which it acts and to generate invertebrate genetic models of spinal muscular atrophy (Briese et al., 2009; Chan et al., 2003; Chang et al., 2008; Rajendra et al., 2007; Sleigh et al., 2011). "
    [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; 78. DOI:10.1016/j.neuropharm.2013.06.015 · 5.11 Impact Factor
  • Source
    • "A less complete removal of smn-1 produces an arrest in late larval development [Fig. 1(A)], reduced lifespan, sterility, and locomotor dysfunction (Briese et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Proximal spinal muscular atrophy, the most frequent genetic cause of childhood lethality, is caused by homozygous loss or mutation of the SMN1 gene on human chromosome 5, which codes for the survival motor neuron (SMN) protein. SMN plays a role in the assembly of small nuclear ribonucleoproteins and, additionally, in synaptic function. SMN deficiency produces defects in motor neuron β-actin mRNA axonal transport, neurofilament dynamics, neurotransmitter release, and synapse maturation. The underlying molecular mechanisms and, in particular, the role of the cytoskeleton on the pathogenesis of this disease are starting to be revealed.
    Developmental Neurobiology 01/2012; 72(1):126-33. DOI:10.1002/dneu.20912 · 3.37 Impact Factor
Show more