Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding
423
Citation
72
Reference
10
Related Paper
Citation Trend
Abstract:
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of α motoneurons in the spinal cord. SMA is caused by low levels of the ubiquitously expressed survival motor neuron (Smn) protein. As it is unclear how low levels of Smn specifically affect motoneurons, we have modeled SMA in zebrafish, a vertebrate model organism with well-characterized motoneuron development. Using antisense morpholinos to reduce Smn levels throughout the entire embryo, we found motor axon–specific pathfinding defects. Reduction of Smn in individual motoneurons revealed that smn is acting cell autonomously. These results show for the first time, in vivo, that Smn functions in motor axon development and suggest that these early developmental defects may lead to subsequent motoneuron loss.Keywords:
Morpholino
SMN1
Cite
Citations (25)
Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by the degeneration of motor neurons in the spinal cord. The disease is caused by mutations of the survival of motor neuron 1 gene (SMN1), resulting in a reduced production of functional SMN protein. A major question unanswered thus far is why reduced amounts of ubiquitously expressed SMN protein specifically cause the degeneration of motor neurons without affecting other somatic cell types. In a first attempt to address this issue we have investigated the Smn interacting protein 1 (Sip1), with an emphasis on its developmental expression and subcellular distribution in spinal motor neurons in relation to Smn. By confocal immunofluorescence studies we provide evidence that a significant amount of Smn does not co-localize with Sip1 in neurites of motor neurons, indicating that Smn may exert motor neuron-specific functions that are not dependent on Sip1. Sip1 is highly expressed in the spinal cord during early development and expression decreases in parallel with Smn during postnatal development. Strikingly, reduced production of Smn as observed in cell lines derived from SMA patients or in a mouse model for SMA coincides with a simultaneous reduction of Sip1. The finding that expression of Sip1 and Smn is tightly co-regulated, together with the unique localization of Smn in neurites, may help in understanding the motor neuron-specific defects observed in SMA patients.
SMN1
Neurite
Cite
Citations (100)
SMN1
Cite
Citations (26)
Spinal muscular atrophy, a common autosomal recessive motor neuron disorder, is caused by the loss of the survival motor neuron gene ( SMN1). SMN2, a nearly identical copy gene, is present in all spinal muscular atrophy patients but differs by a critical nucleotide that alters exon 7 splicing efficiency. This results in low survival motor neuron protein levels, which are not enough to sustain motor neurons. SMN disruption has been undertaken in different organisms (yeast, nematode, fly, zebrafish, and mouse) in an attempt to model this disease and gain fundamental knowledge about the survival motor neuron protein. This review compares the various animal models generated to date and summarizes a research picture that reveals a pleiotropic role for survival motor neuron protein; this summary also points to unique requirements for survival motor neuron protein in motor neurons. It is hoped that these observations will aid in pointing towards complementary paths for therapeutic discovery research.
SMN1
Cite
Citations (54)
OBJECTIVE: The aim of the study is to determine the efficacy of a new designed morpholino (MO) both as bare morpholino and with an octa-guanidine modification in a Spinal Muscular Atrophy (SMA) mouse model.
Morpholino
SMN1
Guanidine
Cite
Citations (0)
Muscle Atrophy
Cite
Citations (22)
Abstract The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron ( SMN ) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well understood, it is not clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies. BioEssays 27:946–957, 2005. © 2005 Wiley Periodicals, Inc.
SMN1
Cite
Citations (98)
Cite
Citations (10)
SMN1
Cite
Citations (37)
Abstract Spinal muscular atrophy ( SMA ) is an autosomal recessive neurodegenerative disease characterized by the selective death of lower motor neurons in the brain stem and spinal cord. SMA is caused by mutations in the survival motor neuron 1 gene ( SMN 1 ), leading to the reduced expression of the full‐length SMN protein. micro RNA s (mi RNA s) are small RNA s that regulate post‐transcriptional gene expression. Recent findings have suggested an important role for mi RNA s in the pathogenesis of motor neuron diseases, including SMA . Motor neuron‐specific mi RNA dysregulation in SMA might be implicated in their selective vulnerability. In this study, we discuss recent findings regarding the consequences of SMN defects on mi RNA s and their target mRNA s in motor neurons. Taken together, these data suggest that cell‐specific changes in mi RNA s are not only involved in the SMA motor neuron phenotype but can also be used as biomarkers and therapeutic targets.
Pathogenesis
Cite
Citations (51)