PUBLICATION

SMN deficiency alters Nrxn2 expression and splicing in zebrafish and mouse models of spinal muscular atrophy

Authors
See, K., Yadav, P., Giegerich, M., Cheong, P.S., Graf, M., Vyas, H., Lee, S.G., Mathavan, S., Fischer, U., Sendtner, M., and Winkler, C.
ID
ZDB-PUB-131218-30
Date
2014
Source
Human molecular genetics   23(7): 1754-70 (Journal)
Registered Authors
Graf, Martin, Mathavan, S., Winkler, Christoph
Keywords
none
Datasets
GEO:GSE47001
MeSH Terms
  • Alternative Splicing/genetics
  • Animals
  • Calcium/metabolism
  • Calcium Signaling
  • Cells, Cultured
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • In Situ Hybridization
  • Laser Capture Microdissection
  • Mice
  • Mice, Transgenic
  • Morpholinos/genetics
  • Motor Neurons/metabolism
  • Muscular Atrophy, Spinal/genetics*
  • Nerve Tissue Proteins/biosynthesis
  • Nerve Tissue Proteins/genetics*
  • Protein Isoforms/genetics
  • RNA, Messenger/genetics
  • Spinal Cord/metabolism
  • Survival of Motor Neuron 1 Protein/genetics*
  • Survival of Motor Neuron 2 Protein/genetics
  • Zebrafish
PubMed
24218366 Full text @ Hum. Mol. Genet.
Abstract

Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease affecting lower motor neurons. SMA is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, which result in reduced levels of functional SMN protein. Biochemical studies have linked the ubiquitously expressed SMN protein to the assembly of pre-mRNA processing U snRNPs, raising the possibility that aberrant splicing is a major defect in SMA. Accordingly, several transcripts affected upon SMN deficiency have been reported. A second function for SMN in axonal mRNA transport has also been proposed that may likewise contribute to the SMA phenotype. The underlying etiology of SMA, however, is still not fully understood. Here, we have used a combination of genomics and live Ca2+ imaging to investigate the consequences of SMN deficiency in a zebrafish model of SMA. In a transcriptome analyses of SMN-deficient zebrafish, we identified neurexin2a (nrxn2a) as strongly down-regulated and displaying changes in alternative splicing patterns. Importantly, the knock-down of two distinct nrxn2a isoforms phenocopies SMN-deficient fish and results in a significant reduction of motor axon excitability. Interestingly, we observed altered expression and splicing of Nrxn2 also in motor neurons from the Smn/;SMN2+/+ mouse model of SMA, suggesting conservation of nrxn2 regulation by SMN in mammals. We propose that SMN deficiency affects splicing and abundance of nrxn2a. This may explain the pre-synaptic defects at neuromuscular endplates in SMA pathophysiology.

Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Errata and Notes