Fragile X Protein Functions With LGL and the Par Complex in Flies and Mice

Dev Cell. 2005 Jan;8(1):43-52. doi: 10.1016/j.devcel.2004.10.020.

Abstract

Fragile X syndrome, the most common form of inherited mental retardation, is caused by loss of function for the Fragile X Mental Retardation 1 gene (FMR1). FMR1 protein (FMRP) has specific mRNA targets and is thought to be involved in their transport to subsynaptic sites as well as translation regulation. We report a saturating genetic screen of the Drosophila autosomal genome to identify functional partners of dFmr1. We recovered 19 mutations in the tumor suppressor lethal (2) giant larvae (dlgl) gene and 90 mutations at other loci. dlgl encodes a cytoskeletal protein involved in cellular polarity and cytoplasmic transport and is regulated by the PAR complex through phosphorylation. We provide direct evidence for a Fmrp/Lgl/mRNA complex, which functions in neural development in flies and is developmentally regulated in mice. Our data suggest that Lgl may regulate Fmrp/mRNA sorting, transport, and anchoring via the PAR complex.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alcohol Oxidoreductases / metabolism*
  • Animals
  • Blotting, Western / methods
  • Cell Fractionation / methods
  • Cells, Cultured
  • Cloning, Molecular / methods
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Drosophila
  • Drosophila Proteins / metabolism*
  • Eye / pathology
  • Eye / ultrastructure
  • Fragile X Mental Retardation Protein
  • Gene Expression Regulation, Developmental
  • Genes, Tumor Suppressor / physiology*
  • Humans
  • Immunohistochemistry / methods
  • Mice
  • Microscopy, Electron, Scanning / methods
  • Mutagenesis
  • Mutation
  • Nerve Tissue Proteins / physiology*
  • Neuromuscular Junction / genetics
  • Neuromuscular Junction / metabolism
  • Oligonucleotide Array Sequence Analysis / methods
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism*
  • RNA-Binding Proteins / physiology*
  • Retina / pathology
  • Retina / ultrastructure
  • Subcellular Fractions / metabolism
  • Synapses / metabolism
  • Time Factors
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Cytoskeletal Proteins
  • Drosophila Proteins
  • FMR1 protein, Drosophila
  • FMR1 protein, human
  • Fmr1 protein, mouse
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • Tumor Suppressor Proteins
  • l(2)gl protein, Drosophila
  • Fragile X Mental Retardation Protein
  • Alcohol Oxidoreductases
  • phenylacetaldehyde reductase