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Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting.

ABSTRACT: During assembly of the Drosophila olfactory circuit, projection neuron (PN) dendrites prepattern the developing antennal lobe before the arrival of axons from their presynaptic partners, the adult olfactory receptor neurons (ORNs). We previously found that levels of transmembrane Semaphorin-1a, which acts as a receptor, instruct PN dendrite targeting along the dorsolateral-ventromedial axis. Here we show that two secreted semaphorins, Sema-2a and Sema-2b, provide spatial cues for PN dendrite targeting. Sema-2a and Sema-2b proteins are distributed in gradients opposing the Sema-1a protein gradient, and Sema-1a binds to Sema-2a-expressing cells. In Sema-2a and Sema-2b double mutants, PN dendrites that normally target dorsolaterally in the antennal lobe mistarget ventromedially, phenocopying cell-autonomous Sema-1a removal from these PNs. Cell ablation, cell-specific knockdown, and rescue experiments indicate that secreted semaphorins from degenerating larval ORN axons direct dendrite targeting. Thus, a degenerating brain structure instructs the wiring of a developing circuit through the repulsive action of secreted semaphorins.

SUBMITTER: Sweeney LB

PROVIDER: S-EPMC3365565 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting.

Sweeney Lora B LB Chou Ya-Hui YH Wu Zhuhao Z Joo William W Komiyama Takaki T Potter Christopher J CJ Kolodkin Alex L AL Garcia K Christopher KC Luo Liqun L

Neuron 20111201 5

During assembly of the Drosophila olfactory circuit, projection neuron (PN) dendrites prepattern the developing antennal lobe before the arrival of axons from their presynaptic partners, the adult olfactory receptor neurons (ORNs). We previously found that levels of transmembrane Semaphorin-1a, which acts as a receptor, instruct PN dendrite targeting along the dorsolateral-ventromedial axis. Here we show that two secreted semaphorins, Sema-2a and Sema-2b, provide spatial cues for PN dendrite tar ...[more]

PMID: 22153371

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Project description:SARM1 is the central executioner of pathological axon degeneration, promoting axonal demise in response to axotomy, traumatic brain injury, and neurotoxic chemotherapeutics that induce peripheral neuropathy. SARM1 is an injury-activated NAD+ cleavage enzyme, and this NADase activity is required for the pro-degenerative function of SARM1. At present, SARM1 function is assayed by either analysis of axonal loss, which is far downstream of SARM1 enzymatic activity, or via NAD+ levels, which are regulated by many competing pathways. Here we explored the utility of measuring cADPR, a product of SARM1-dependent cleavage of NAD+, as an in cell and in vivo biomarker of SARM1 enzymatic activity. We find that SARM1 is a major producer of cADPR in cultured dorsal root ganglion (DRG) neurons, sciatic nerve, and brain, demonstrating that SARM1 has basal activity in the absence of injury. Following injury, there is a dramatic SARM1-dependent increase in the levels of axonal cADPR that precedes morphological axon degeneration. In vivo, there is also a rapid and large injury-stimulated increase in cADPR in sciatic and optic nerves. The increase in cADPR after injury is proportional to SARM1 gene dosage, suggesting that SARM1 activity is the prime regulator of cADPR levels. The role of cADPR as an important calcium mobilizing agent prompted exploration of its functional contribution to axon degeneration. We used multiple bacterial and mammalian engineered enzymes to manipulate cADPR levels in neurons but found no changes in the time course of axonal degeneration, suggesting that cADPR is unlikely to be an important contributor to the degenerative mechanism. Using cADPR as a SARM1 biomarker, we find that SARM1 can be partially activated by a diverse array of mitochondrial toxins administered at doses that do not induce axon degeneration. Hence, the subcritical activation of SARM1 induced by mitochondrial dysfunction may contribute to the axonal vulnerability common to many neurodegenerative diseases. Finally, we assay levels of both nerve cADPR and plasma neurofilament light chain (NfL) following nerve injury in vivo, and demonstrate that both biomarkers are excellent readouts of SARM1 activity, with cADPR reporting the early molecular changes in the nerve and NfL reporting subsequent axonal breakdown. The identification and characterization of cADPR as a SARM1 biomarker will help identify neurodegenerative diseases in which SARM1 contributes to axonal loss and expedite target validation studies of SARM1-directed therapeutics.

Dataset Information

Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting.

Publications

Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting.

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