SMN deficiency disrupts brain development in a mouse model of severe spinal muscular atrophy

Thomas M. Wishart, Jack P. -W. Huang, Lyndsay M. Murray, Douglas J. Lamont, Chantal A. Mutsaers, Jenny Ross, Pascal Geldsetzer, Olaf Ansorge, Kevin Talbot, Simon H. Parson, Thomas H. Gillingwater*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)

Abstract

Reduced expression of the survival motor neuron (SMN) gene causes the childhood motor neuron disease spinal muscular atrophy (SMA). Low levels of ubiquitously expressed SMN protein result in the degeneration of lower motor neurons, but it remains unclear whether other regions of the nervous system are also affected. Here we show that reduced levels of SMN lead to impaired perinatal brain development in a mouse model of severe SMA. Regionally selective changes in brain morphology were apparent in areas normally associated with higher SMN levels in the healthy postnatal brain, including the hippocampus, and were associated with decreased cell density, reduced cell proliferation and impaired hippocampal neurogenesis. A comparative proteomics analysis of the hippocampus from SMA and wild-type littermate mice revealed widespread modifications in expression levels of proteins regulating cellular proliferation, migration and development when SMN levels were reduced. This study reveals novel roles for SMN protein in brain development and maintenance and provides the first insights into cellular and molecular pathways disrupted in the brain in a severe form of SMA.

Original languageEnglish
Pages (from-to)4216-4228
Number of pages13
JournalHuman Molecular Genetics
Volume19
Issue number21
Early online date12 Aug 2010
DOIs
Publication statusPublished - 1 Nov 2010

Keywords

  • Werdnig-Hoffmann-disease
  • determining gene
  • Wallerian degeneration
  • motor-neurons
  • protein
  • neurogenesis
  • pathology
  • vulnerability
  • expression
  • defects

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