Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy

Zhenxi Zhang, Anna Maria Pinto, Lili Wan, Wei Wang, Michael G. Berg, Isabela Oliva, Larry N. Singh, Christopher Dengler, Zhi Wei, Gideon Dreyfuss

Research output: Contribution to journalArticlepeer-review

147 Scopus citations


The motor neuron (MN) degenerative disease, spinal muscular atrophy (SMA) is caused by deficiency of SMN (survival motor neuron), a ubiquitous and indispensable protein essential for biogenesis of snRNPs, key components of pre-mRNA processing. However, SMA's hallmark MN pathology, including neuromuscular junction (NMJ) disruption and sensory-motor circuitry impairment, remains unexplained. Toward this end, we used deep RNA sequencing (RNA-seq) to determine if there are any transcriptome changes in MNs and surrounding spinal cord glial cells (white matter, WM) microdissected from SMN-deficient SMA mouse model at presymptomatic postnatal day 1 (P1), before detectableMN pathology (P4-P5). The RNA-seq results, previously unavailable for SMA at any stage, revealed cell-specific selective mRNA dysregulations (~300 of 11,000 expressed genes in each, MN and WM), many of which are known to impair neurons. Remarkably, these dysregulations include complete skipping of agrin's Z exons, critical for NMJ maintenance, strong upregulation of synapse pruning-promoting complement factor C1q, and down-regulation of Etv1/ER81, a transcription factor required for establishing sensory-motor circuitry. We propose that dysregulation of such specificMN synaptogenesis genes, compounded bymany additional transcriptome abnormalities in MNs and WM, link SMN deficiency to SMA's signature pathology.

Original languageEnglish (US)
Pages (from-to)19348-19353
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number48
StatePublished - Nov 26 2013
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


  • C1q complex
  • Transcriptome perturbations
  • Z+ (neuronal) agrin


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