The Conserved, Disease-Associated RNA Binding Protein dNab2 Interacts with the Fragile X Protein Ortholog in Drosophila Neurons

Cell Rep. 2017 Aug 8;20(6):1372-1384. doi: 10.1016/j.celrep.2017.07.038.

Abstract

The Drosophila dNab2 protein is an ortholog of human ZC3H14, a poly(A) RNA binding protein required for intellectual function. dNab2 supports memory and axon projection, but its molecular role in neurons is undefined. Here, we present a network of interactions that links dNab2 to cytoplasmic control of neuronal mRNAs in conjunction with the fragile X protein ortholog dFMRP. dNab2 and dfmr1 interact genetically in control of neurodevelopment and olfactory memory, and their encoded proteins co-localize in puncta within neuronal processes. dNab2 regulates CaMKII, but not futsch, implying a selective role in control of dFMRP-bound transcripts. Reciprocally, dFMRP and vertebrate FMRP restrict mRNA poly(A) tail length, similar to dNab2/ZC3H14. Parallel studies of murine hippocampal neurons indicate that ZC3H14 is also a cytoplasmic regulator of neuronal mRNAs. Altogether, these findings suggest that dNab2 represses expression of a subset of dFMRP-target mRNAs, which could underlie brain-specific defects in patients lacking ZC3H14.

Keywords: CamKII; Drosophila; RNA binding protein; ZC3H14; dNab2; fragile X mental retardation protein; futsch; memory; neurodevelopment; poly(A) tail.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Drosophila
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Mental Retardation Protein / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Regulatory Networks*
  • Male
  • Memory
  • Mice
  • Neurons / metabolism*
  • Neurons / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Smell

Substances

  • Drosophila Proteins
  • FMR1 protein, Drosophila
  • Nab2 protein, Drosophila
  • RNA, Messenger
  • RNA-Binding Proteins
  • Fragile X Mental Retardation Protein
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2