The fragile X-related gene affects the crawling behavior of Drosophila larvae by regulating the mRNA level of the DEG/ENaC protein pickpocket1

Curr Biol. 2004 Jun 22;14(12):1025-34. doi: 10.1016/j.cub.2004.05.055.


Background: Fragile X syndrome is caused by loss-of-function mutations in the fragile X mental retardation 1 (FMR1) gene. How FMR1 affects the function of the central and peripheral nervous systems is still unclear. FMR1 is an RNA binding protein that associates with a small percentage of total mRNAs in vivo. It remains largely unknown what proteins encoded by mRNAs in the FMR1-messenger ribonuclear protein (mRNP) complex are most relevant to the affected physiological processes.

Results: Loss-of-function mutations in the Drosophila fragile X-related (dfmr1) gene, which is highly homologous to the human fmr1 gene, decrease the duration and percentage of time that crawling larvae spend on linear locomotion. Overexpression of DFMR1 in multiple dendritic (MD) sensory neurons increases the time percentage and duration of linear locomotion; this phenotype is similar to that caused by reduced expression of the MD neuron subtype-specific degenerin/epithelial sodium channel (DEG/ENaC) family protein Pickpocket1 (PPK1). Genetic analyses indicate that PPK1 is a key component downstream of DFMR1 in controlling the crawling behavior of Drosophila larvae. DFMR1 and ppk1 mRNA are present in the same mRNP complex in vivo and can directly bind to each other in vitro. DFMR1 downregulates the level of ppk1 mRNA in vivo, and this regulatory process also involves Argonaute2 (Ago2), a key component in the RNA interference pathway.

Conclusions: These studies identify ppk1 mRNA as a physiologically relevant in vivo target of DFMR1. Our finding that the level of ppk1 mRNA is regulated by DFMR1 and Ago2 reveals a genetic pathway that controls sensory input-modulated locomotion behavior.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Argonaute Proteins
  • Crosses, Genetic
  • DNA Primers
  • DNA, Complementary / genetics
  • Drosophila
  • Drosophila Proteins / metabolism
  • Electrophoresis, Agar Gel
  • Fragile X Mental Retardation Protein
  • Gene Expression Regulation*
  • Larva / physiology
  • Locomotion / genetics
  • Locomotion / physiology*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Nerve Tissue Proteins / physiology
  • Neurons, Afferent / metabolism
  • Precipitin Tests
  • RNA Interference / physiology
  • RNA, Messenger / metabolism*
  • RNA-Binding Proteins*
  • RNA-Induced Silencing Complex / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribonucleoproteins / metabolism*
  • Sodium Channels / genetics
  • Sodium Channels / metabolism*


  • AGO2 protein, Drosophila
  • Argonaute Proteins
  • DNA Primers
  • DNA, Complementary
  • Drosophila Proteins
  • Nerve Tissue Proteins
  • RNA, Messenger
  • RNA-Binding Proteins
  • RNA-Induced Silencing Complex
  • Ribonucleoproteins
  • Sodium Channels
  • messenger ribonucleoprotein
  • Fragile X Mental Retardation Protein