Mechanistic relationships between Drosophila fragile X mental retardation protein and metabotropic glutamate receptor A signaling.
Fragile X syndrome is caused by loss of the FMRP translational regulator. A current hypothesis proposes that FMRP functions downstream of mGluR signaling to regulate synaptic connections. Using the Drosophila disease model, we test relationships between dFMRP and the sole Drosophila mGluR (DmGluRA) by assaying protein expression, behavior and neuron structure in brain and NMJ; in single mutants, double mutants and with an mGluR antagonist. At the protein level, dFMRP is upregulated in dmGluRA mutants, and DmGluRA is upregulated in dfmr1 mutants, demonstrating mutual negative feedback. Null dmGluRA mutants display defects in coordinated movement behavior, which are rescued by removing dFMRP expression. Null dfmr1 mutants display increased NMJ presynaptic structural complexity and elevated presynaptic vesicle pools, which are rescued by blocking mGluR signaling. Null dfmr1 brain neurons similarly display increased presynaptic architectural complexity, which is rescued by blocking mGluR signaling. These data show that DmGluRA and dFMRP convergently regulate presynaptic properties.
Pan
Luyuan
L
Department of Biological Science, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232, USA.
Woodruff
Elvin
E
Liang
Ping
P
Broadie
Kendal
K
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D009068:Movement / Q000502:physiology; D009154:Mutation; D009469:Neuromuscular Junction / Q000502:physiology* / Q000648:ultrastructure; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D029721:Drosophila Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D018094:Receptors, Metabotropic Glutamate; C494781:mGluR protein, Drosophila