The spinal muscular atrophy gene product regulates neurite outgrowth: importance of the C terminus

Bergeijk, J. van; Rydel-Könecke, Katharina; Grothe, Claudia; Claus, Piet

doi:10.1096/fj.06-7136com

Cited by 56 publications

(53 citation statements)

References 64 publications

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“…These data indicate that the number or structural integrity of gems may not be directly relevant to SMA disease progression. Instead, other nuclear or axonal SMN functions could be responsible for motor neuron degeneration (38)(39)(40)(41)(42)(43)(44). Furthermore, only a subset of SMN molecules is bound by FGF-2 23 (21,22).…”

Section: Discussionmentioning

confidence: 99%

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Fibroblast growth factor–2 regulates the stability of nuclear bodies

Bruns

Bergeijk

Lorbeer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Nuclear bodies are distinct subnuclear structures. The survival of motoneuron (SMN) gene is mutated or deleted in patients with the neurodegenerative disease spinal muscular atrophy (SMA). The gene product SMN is a marker protein for one class of nuclear bodies denoted as nuclear gems. SMN has also been found in Cajal bodies, which co-localize with gems in many cell types. Interestingly, SMA patients display a reduced number of gems. Little is known about the regulation of nuclear body formation and stabilization. We have previously shown that a nuclear isoform of the fibroblast growth factor-2 (FGF-2 23 ) binds directly to SMN. In this study, we analyzed the consequences of FGF-2 23 binding to SMN with regard to nuclear body formation. On a molecular level, we showed that FGF-2 23 competed with Gemin2 (a component of the SMN complex that is necessary for gem stabilization) for binding to SMN. Down-regulation of Gemin2 by siRNA caused destabilization of SMN-positive nuclear bodies. This process is reflected in both cellular and in vivo systems by a negative regulatory function of FGF-2 in nuclear body formation: in HEK293 cells, FGF-2 23 decreased the number of SMN-positive nuclear bodies. The same effect could be observed in motoneurons of FGF-2 transgenic mice. This study demonstrates the functional role of a growth factor in the regulation of structural entities of the nucleus. nuclear organization ͉ nuclear structure ͉ spinal muscular atrophy ͉ survival of motoneuron protein

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Section: Discussionmentioning

confidence: 99%

“…Full-length human SMN pSMN1-294-EGFP and the mutants pSMN1-239-EGFP and pSMN235-294-EGFP were described before (43). For expression of Gemin2, a complete cDNA contained in pCMV-SPORT6 was used.…”

Section: Methodsmentioning

confidence: 99%

Fibroblast growth factor–2 regulates the stability of nuclear bodies

Bruns

Bergeijk

Lorbeer

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Interestingly, defects in actin organization have also been observed in SMN-depleted PC12 cells. While one study demonstrated an accumulation of F-actin at the cell periphery [94], another showed a change in G-/F-actin ratio due to an increase in the F-actin component [74]. Whether the above-described defects in actin organization are directly or indirectly due to the regulation of actin mRNA still needs to be established.…”

Section: B-actin Mrna Axonal Transportmentioning

confidence: 98%

“…Interestingly, SMN expression increases in both murine neurosphere-derived neural stem cells and PC12 cells during neuronal differentiation [72,74]. Fan and Simard reported that SMN localizes in growth cones of mouse embryonal teratocarcinoma P19 cells during neuronal differentiation [70].…”

Section: Smn Function and Sma Pathology In Motor Neuronsmentioning

confidence: 99%

“…The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis Review leads to the absence of SMN outside the nucleus and was consequently coupled with a decrease in neurite outgrowth [74,75]. Additional work performed in PC12 cells and in primary cultures of mouse motor neurons supports a role for SMN in neuronal outgrowth [76].…”

Section: Smn Function and Sma Pathology In Motor Neuronsmentioning

confidence: 99%

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The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis

2010

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Spinal muscular atrophy (SMA) is the leading genetic cause of infant death, affecting 1 in 6000-10,000 live births. SMA is an autosomal recessive disorder characterized by the degeneration of a-motor neurons, and lower limb and proximal muscle weakness and wasting. SMA is the result of the deletion of or mutations in the survival motor neuron (SMN)1 gene. Currently, our understanding of how loss of the widely expressed SMN leads to the selective pathogenesis observed in SMA is limited. Here, we discuss the known nuclear and cytoplasmic functions of the SMN protein and how they relate to the SMA pathology reported in motor neurons, striated muscle and at neuromuscular junctions. While a vast amount of work in various cell and animal models has increased our knowledge of the many functions of the SMN protein, we have yet to come to a full understanding of which role(s) are central to SMA pathogenesis.Keywords n actin dynamics n neurodegeneration n preclinical models n snRNP assembly n spinal muscular atrophy n survival motor neuron ReviewFor reprint orders, please contact: reprints@futuremedicine.com

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Neurodevelopmental abnormalities in neurosphere‐derived neural stem cells from SMN‐depleted mice

Shafey

MacKenzie

Kothary

2008

J of Neuroscience Research

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Spinal muscular atrophy (SMA) is a genetic disorder caused by depletion of survival motor neuron (SMN) protein and characterized by degeneration of alpha-motor neurons in the spinal cord. We investigated the morphology and differentiation of neurosphere-derived neural stem cells (NSCs) generated from the brains of a hypomorphic series of SMA mice. Neurospheres from the Smn(-/-);SMN2 mice, which represent a model of very severe SMA, produced NSCs with increased proliferation during growth and differentiation. These cells produced fewer Tuj1-positive neuronal cells, which displayed morphological alterations and had fewer and shorter neurites. The decrease in the number of Tuj1-positive cells was not a result of enhanced apoptosis but was accompanied by an increase in the number of nestin-positive cells. These results provide insight into the most severe model of SMA, in which SMN is nearly completely depleted, and suggest that SMN has a role in neurodevelopment as well as in neuromaintenance. Our work raises the possibility that SMN depletion affects neurodevelopment and neuromaintenance to varying extents, leading to SMA pathogenesis.

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The spinal muscular atrophy gene product regulates neurite outgrowth: importance of the C terminus

Cited by 56 publications

References 64 publications

Fibroblast growth factor–2 regulates the stability of nuclear bodies

Fibroblast growth factor–2 regulates the stability of nuclear bodies

The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis

Neurodevelopmental abnormalities in neurosphere‐derived neural stem cells from SMN‐depleted mice

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