Comparison of parallel high-throughput RNA sequencing between knockout of TDP-43 and its overexpression reveals primarily nonreciprocal and nonoverlapping gene expression changes in the central nervous system of drosophila

Dennis J. Hazelett, Jer Cherng Chang, Daniel L. Lakeland, David B. Morton

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The human Tar-DNA binding protein, TDP-43, is associated with amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. TDP-43 contains two conserved RNA-binding motifs and has documented roles in RNA metabolism, including pre-mRNA splicing and repression of transcription. Here, using Drosophila melanogaster as a model, we generated loss-of-function and overexpression genotypes of Tar-DNA binding protein homolog (TBPH) to study their effect on the transcriptome of the central nervous system (CNS). By using massively parallel sequencing methods (RNA-seq) to profile the CNS, we find that loss of TBPH results in widespread gene activation and altered splicing, much of which are reversed by rescue of TBPH expression. Conversely, TBPH overexpression results in decreased gene expression. Although previous studies implicated both absence and mis-expression of TDP-43 in ALS, our data exhibit little overlap in the gene expression between them, suggesting that the bulk of genes affected by TBPH loss-of-function and overexpression are different. In combination with computational approaches to identify likely TBPH targets and orthologs of previously identified vertebrate TDP-43 targets, we provide a comprehensive analysis of enriched gene ontologies. Our data suggest that TDP-43 plays a role in synaptic transmission, synaptic release, and endocytosis. We also uncovered a potential novel regulation of the Wnt and BMP pathways, many of whose targets appear to be conserved.

Original languageEnglish (US)
Pages (from-to)789-802
Number of pages14
JournalG3: Genes, Genomes, Genetics
Volume2
Issue number7
DOIs
StatePublished - Jul 2012

Keywords

  • Invertebrate
  • Models of human disease
  • Neurodegeneration
  • Neuropathy
  • RNA binding protein genomics
  • TARDBP

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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