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

Proceedings of the National Academy of Sciences of the United States of America (2013-11-06)
Zhenxi Zhang, Anna Maria Pinto, Lili Wan, Wei Wang, Michael G Berg, Isabela Oliva, Larry N Singh, Christopher Dengler, Zhi Wei, Gideon Dreyfuss
RESUMEN

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 detectable MN 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 up-regulation 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 specific MN synaptogenesis genes, compounded by many additional transcriptome abnormalities in MNs and WM, link SMN deficiency to SMA's signature pathology.

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Sigma-Aldrich
Complement component C1q from human serum, ≥95% (SDS-PAGE)
Sigma-Aldrich
Anti-Agrin Antibody, Chemicon®, from mouse