Survival motor neuron (SMN) protein: role in neurite outgrowth and neuromuscular maturation during neuronal differentiation and development

Fan, Li; Simard, Louise R.

doi:10.1093/hmg/11.14.1605

Cited by 155 publications

(115 citation statements)

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“…However, SMN deficiency causes profound effects only on motoneurons but not on other cell types. SMN also exists in the axonal compartment of motoneurons where it is associated with heterogeneous nuclear RNP R and interacts with the 3 0 untranslated region of b-actin mRNA [11][12][13][14]. Reduced SMN results in lower levels of b-actin mRNA and protein in axons and growth cones.…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

et al. 2011

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Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders in humans and is a common genetic cause of infant mortality. The disease is caused by loss of the survival of motoneuron (SMN) protein, resulting in the degeneration of alpha motoneurons in spinal cord and muscular atrophy in the limbs and trunk. One function of SMN involves RNA splicing. It is unclear why a deficiency in a housekeeping function such as RNA splicing causes profound effects only on motoneurons but not on other cell types. One difficulty in studying SMA is the scarcity of patient's samples. The discovery that somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) raises the intriguing possibility of modeling human diseases in vitro. We reported the establishment of five iPSC lines from the fibroblasts of a type 1 SMA patient. Neuronal cultures derived from these SMA iPSC lines exhibited a reduced capacity to form motoneurons and an abnormality in neurite outgrowth. Ectopic SMN expression in these iPSC lines restored normal motoneuron differentiation and rescued the phenotype of delayed neurite outgrowth. These results suggest that the observed abnormalities are indeed caused by SMN deficiency and not by iPSC clonal variability. Further characterization of the cellular and functional deficits in motoneurons derived from these iPSCs may accelerate the exploration of the underlying mechanisms of SMA pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

et al. 2011

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“…Then, SMN protein was found to be present at axon branching points and growth cones in cultured motoneurons [24,39]. In a more detailed analysis that Rossoll and collaborators performed in nPC12 cells, is was found that Smn colocalizes with hnRNPR in cell bodies and neurite-like proceses [68].…”

Section: Smn Protein and Its Functionsmentioning

confidence: 98%

“…The first suggestion that SMN protein might have other important functions than snRNP assembly came from electronmicroscopical analysis of mouse spinal cord that revealed SMN protein present in dendrites and axons [64]. Further analysis of the subcellular localization of SMN during retinoic-acidinduced neuronal differentiation of mouse teratocarcinoma P19 cells demonstrated SMN accumulation in growth cone and filopodia in both neuronal-and glial-like cells [24].…”

Section: Smn Protein and Its Functionsmentioning

confidence: 99%

“…This hypothesis stems from observations demonstrating the accumulation of the SMN protein in the axons and growth cones of motor neuron like cells in vitro and anterior horn cells in vivo [6,7,10,11,24,30,54,64,68,74,94], and its interaction with the heterogeneous nuclear riboprotein Q and R (hnRNP-R) and β-actin mRNA, targeting them into the growth cones [68]. According to the pathogenetic model proposed in this review, the selective motoneuron axonopathy appears to be far more important than ubiquitous nuclear splicing deficit.…”

Section: Two Hypotheses On Sma Pathogenesismentioning

confidence: 99%

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Pathogenesis of proximal autosomal recessive spinal muscular atrophy

Šimić

2008

Acta Neuropathol

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Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new findings regarding the dual cellular role of the SMN protein (translocation of β-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axonoand dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally ("heterotopic motoneurons") and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss.

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“…In neurons, SMN protein is localized in axonal and dendritic processes, in the cytosol mainly bound to microsomes and in the cytoplasmic side of nuclear pores [Cisterni et al, 2001]. In motor neurons, SMN is localized in growth cones, along the axon and in the pre-and post-synaptic sides of the neuromuscular junctions (NMJs) [Francis et al, 1998;Broccolini et al, 1999; La Bella et al, 2000;Pagliardini et al, 2000;Fan and Rossoll et al, 2002] where it forms a macromolecular complex distinct from the nuclear SMN complex [Zhang et al, 2006]. The SMN protein is subject to cytoskeletal-based, bidirectional transport between the soma and growth cones suggesting that SMN may have a cytoplasmic function related to neuronal transport of proteins and mRNA required at the distal tips of axons [Zhang et al, 2003;Rossoll et al, 2003; Jablonka et al, 2004;Fallini et al, 2012].…”

Section: Smn: How Many Functions Can a Single Protein Possess?mentioning

confidence: 99%

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

Tiziano

Melki

Simard

2013

American J of Med Genetics Pt A

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Spinal muscular atrophy (SMA) is an autosomal recessive, lower motor neuron disease. Clinical heterogeneity is pervasive: three infantile (type I-III) and one adult-onset (type IV) forms are recognized. Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA. Most forms of SMA are caused by mutations of the survival motor neuron (SMN1) gene. A second gene that is 99% identical to SMN1 (SMN2) is located in the same region. The only functionally relevant difference between the two genes identified to date is a C ! T transition in exon 7 of SMN2, which determines an alternative spliced isoform that predominantly excludes exon 7. Thus, SMN2 genes do not produce sufficient full length SMN protein to prevent the onset of the disease. Since the identification of the causative mutation, biomedical research of SMA has progressed by leaps and bounds: from clues on the function of SMN protein, to the development of different models of the disease, to the identification of potential treatments, some of which are currently in human trials. The aim of this review is to elucidate the current state of knowledge, emphasizing how close we are to the solution of the puzzle that is SMA, and, more importantly, to highlight the missing pieces of this puzzle. Filling in these gaps in our knowledge will likely accelerate the development and delivery of efficient treatments for SMA patients and be a prerequisite towards achieving our final goal, the cure of SMA. Ó 2013 Wiley Periodicals, Inc. Key words: spinal muscular atrophy; SMN INTRODUCTIONSpinal muscular atrophy (SMA) is a lower motor neuron disease that predominantly affects spinal cord anterior horn cells and brain stem nuclei [Dubowitz, 1995; reviewed in Hamilton and Gillingwater, 2013]. Alpha-motor neuron cell degeneration results in progressive, symmetrical skeletal muscle atrophy of limbs and trunk, spreading proximal to distal [Crawford and Pardo, 1996]. Clinical heterogeneity is pervasive: based on the age of onset and on the maximum motor achievement of patients, three infantile (type I-III) and one adult-onset (type IV) forms are commonly recognized. Classification criteria are summarized in Table I. However, this rigid classification does not accurately depict the range of SMA clinical phenotypes, which display a more continuous spectrum, ranging from prenatal onset to almost asymptomatic patients. SMA is a common autosomal recessive disorder (incidence is $1 in 6,000 in most ethnicities). Type I SMA is the most common genetic cause of death in infancy and accounts for about 50% of all patients with SMA [Crawford and Pardo, 1996;Prior, 2010].Most forms of SMA are caused by mutations in the survival motor neuron (SMN) gene, which was isolated in 1995 in chromosome 5q13 harboring a segmental duplication [Lefebvre et al., 1995]. Mutations in SMN1 are responsible for the four forms of SMA [Wirth, 2000;Alías et al., 2009]. A second gene that is 99% identical to SMN1, the SMN2 gene, is located in the same region [Le...

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Survival motor neuron (SMN) protein: role in neurite outgrowth and neuromuscular maturation during neuronal differentiation and development

Cited by 155 publications

References 69 publications

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

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