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Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding.

McWhorter ML, Monani UR, Burghes AH, Beattie CE - J. Cell Biol. (2003)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Neurobiology, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of alpha 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.

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AChR clustering is normal when Smn is decreased. Lateral views of znp1 (A and D; motor axons, green) mAb, α-bungarotoxin (B and E; AChR, red) stained, and merge (C and F; yellow) 74-h larvae injected with control MO (A–C; n = 18) or smn MO (D–F; n = 49). Aberrant motor nerve (arrowhead) retains ability to cluster AChR. Bar, 50 μm.
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fig8: AChR clustering is normal when Smn is decreased. Lateral views of znp1 (A and D; motor axons, green) mAb, α-bungarotoxin (B and E; AChR, red) stained, and merge (C and F; yellow) 74-h larvae injected with control MO (A–C; n = 18) or smn MO (D–F; n = 49). Aberrant motor nerve (arrowhead) retains ability to cluster AChR. Bar, 50 μm.

Mentions: As motor axons in smn MO embryos displayed aberrant axon outgrowth, we asked whether these axons were still capable of forming synapses on the muscle fibers. To address this, we analyzed acetylcholine receptor (AChR) clusters in smn MO embryos at 3 d. Using rhodamine-conjugated α-bungarotoxin, we found that all axons in smn MO and control MO embryos colocalized with AChR clusters (Fig. 8, A–F), suggesting that the axons are innervating muscle fibers but lack the stereotyped pattern of innervation (Fig. 8, D–F, arrows). Consistent with this observation, we found no overt movement defects or paralysis in these embryos (unpublished data).


Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding.

McWhorter ML, Monani UR, Burghes AH, Beattie CE - J. Cell Biol. (2003)

AChR clustering is normal when Smn is decreased. Lateral views of znp1 (A and D; motor axons, green) mAb, α-bungarotoxin (B and E; AChR, red) stained, and merge (C and F; yellow) 74-h larvae injected with control MO (A–C; n = 18) or smn MO (D–F; n = 49). Aberrant motor nerve (arrowhead) retains ability to cluster AChR. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1761110&req=5

fig8: AChR clustering is normal when Smn is decreased. Lateral views of znp1 (A and D; motor axons, green) mAb, α-bungarotoxin (B and E; AChR, red) stained, and merge (C and F; yellow) 74-h larvae injected with control MO (A–C; n = 18) or smn MO (D–F; n = 49). Aberrant motor nerve (arrowhead) retains ability to cluster AChR. Bar, 50 μm.
Mentions: As motor axons in smn MO embryos displayed aberrant axon outgrowth, we asked whether these axons were still capable of forming synapses on the muscle fibers. To address this, we analyzed acetylcholine receptor (AChR) clusters in smn MO embryos at 3 d. Using rhodamine-conjugated α-bungarotoxin, we found that all axons in smn MO and control MO embryos colocalized with AChR clusters (Fig. 8, A–F), suggesting that the axons are innervating muscle fibers but lack the stereotyped pattern of innervation (Fig. 8, D–F, arrows). Consistent with this observation, we found no overt movement defects or paralysis in these embryos (unpublished data).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Center for Molecular Neurobiology, The Ohio State University, Columbus, OH 43210, USA.

ABSTRACT
Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by a loss of alpha 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.

Show MeSH
Related in: MedlinePlus