title: Dysregulation of synaptogenesis genes antecedes motor neuron pathology in spinal muscular atrophy.
abstract: 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.
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6148.
authors.forename: Zhenxi
authors.initials: Z
authors.lastname: Zhang
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pinto
authors.forename: Lili
authors.initials: L
authors.lastname: Wan
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Michael G
authors.initials: MG
authors.lastname: Berg
authors.forename: Isabela
authors.initials: I
authors.lastname: Oliva
authors.forename: Larry N
authors.initials: LN
authors.lastname: Singh
authors.forename: Christopher
authors.initials: C
authors.lastname: Dengler
authors.forename: Zhi
authors.initials: Z
authors.lastname: Wei
authors.forename: Gideon
authors.initials: G
authors.lastname: Dreyfuss
mesh_terms: D000818:Animals; D001483:Base Sequence; D015922:Complement C1q / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D009457:Neuroglia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D055532:SMN Complex Proteins / Q000172:deficiency* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C490641:Etv1 protein, mouse; D012333:RNA, Messenger; D055532:SMN Complex Proteins; D014157:Transcription Factors; D015922:Complement C1q
keywords: C1q complex; Z+ (neuronal) agrin; transcriptome perturbations