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The BMP ligand Gbb gates the expression of synaptic homeostasis independent of synaptic growth control.

ABSTRACT: Inhibition of postsynaptic glutamate receptors at the Drosophila NMJ initiates a compensatory increase in presynaptic release termed synaptic homeostasis. BMP signaling is necessary for normal synaptic growth and stability. It remains unknown whether BMPs have a specific role during synaptic homeostasis and, if so, whether BMP signaling functions as an instructive retrograde signal that directly modulates presynaptic transmitter release. Here, we demonstrate that the BMP receptor (Wit) and ligand (Gbb) are necessary for the rapid induction of synaptic homeostasis. We also provide evidence that both Wit and Gbb have functions during synaptic homeostasis that are separable from NMJ growth. However, further genetic experiments demonstrate that Gbb does not function as an instructive retrograde signal during synaptic homeostasis. Rather, our data indicate that Wit and Gbb function via the downstream transcription factor Mad and that Mad-mediated signaling is continuously required during development to confer competence of motoneurons to express synaptic homeostasis.

SUBMITTER: Goold CP

PROVIDER: S-EPMC2699048 | biostudies-literature | 2007 Oct

REPOSITORIES: biostudies-literature

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The BMP ligand Gbb gates the expression of synaptic homeostasis independent of synaptic growth control.

Goold Carleton P CP Davis Graeme W GW

Neuron 20071001 1

Inhibition of postsynaptic glutamate receptors at the Drosophila NMJ initiates a compensatory increase in presynaptic release termed synaptic homeostasis. BMP signaling is necessary for normal synaptic growth and stability. It remains unknown whether BMPs have a specific role during synaptic homeostasis and, if so, whether BMP signaling functions as an instructive retrograde signal that directly modulates presynaptic transmitter release. Here, we demonstrate that the BMP receptor (Wit) and ligan ...[more]

PMID: 17920019

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Project description:Huntington's disease (HD) is a neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) stretch within the Huntingtin (Htt) protein. Pathogenic Htt disrupts multiple neuronal processes, including gene expression, axonal trafficking, proteasome and mitochondrial activity, and intracellular vesicle trafficking. However, the primary pathogenic mechanism and subcellular site of action for mutant Htt are still unclear. Using a Drosophila HD model, we found that pathogenic Htt expression leads to a profound overgrowth of synaptic connections that correlates directly with the levels of Htt at nerve terminals. Branches of the same nerve containing different levels of Htt show distinct phenotypes, indicating that Htt acts locally to disrupt synaptic growth. The effects of pathogenic Htt on synaptic growth arise from defective synaptic endosomal trafficking, leading to expansion of a recycling endosomal signaling compartment containing Sorting Nexin 16 and a reduction in late endosomes containing Rab11. The disruption of endosomal compartments leads to elevated BMP signaling within nerve terminals, driving excessive synaptic growth. Blocking aberrant signaling from endosomes or reducing BMP activity ameliorates the severity of HD pathology and improves viability. Pathogenic Htt is present largely in a nonaggregated form at synapses, indicating that cytosolic forms of the protein are likely to be the toxic species that disrupt endosomal signaling. Our data indicate that pathogenic Htt acts locally at nerve terminals to alter trafficking between endosomal compartments, leading to defects in synaptic structure that correlate with pathogenesis and lethality in the Drosophila HD model.SIGNIFICANCE STATEMENT Huntington's disease (HD) is the most commonly inherited polyglutamine expansion disorder, but how mutant Huntingtin (Htt) disrupts neuronal function is unclear. In particular, it is unknown within what subcellular compartment pathogenic Htt acts and whether the pathogenesis is associated with aggregated or more soluble forms of the protein. Using a Drosophila HD model, we find that nonaggregated pathogenic Htt acts locally at synaptic terminals to disrupt endosomal compartments, leading to aberrant wiring defects. Genetic manipulations to increase endosomal trafficking of synaptic growth receptors from signaling endosomes or to reduce BMP signaling reduce pathology in this HD model. These data indicate that pathogenic Htt can act locally within nerve terminals to disrupt synaptic endosomal signaling and induce neuropathology.

Dataset Information

The BMP ligand Gbb gates the expression of synaptic homeostasis independent of synaptic growth control.

Publications

The BMP ligand Gbb gates the expression of synaptic homeostasis independent of synaptic growth control.

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