Abstract
The Pam/Highwire/RPM-1 (PHR) proteins are conserved intracellular signaling hubs that regulate synapse formation and axon termination. The C. elegans PHR protein, called RPM-1, acts as a ubiquitin ligase to inhibit the DLK-1 and MLK-1 MAP kinase pathways. We have identified several kinases that are likely to form a new MAP kinase pathway that suppresses synapse formation defects, but not axon termination defects, in the mechanosensory neurons of rpm-1 mutants. This pathway includes: MIG-15 (MAP4K), NSY-1 (MAP3K), JKK-1 (MAP2K) and JNK-1 (MAPK). Transgenic overexpression of kinases in the MIG-15/JNK-1 pathway is sufficient to impair synapse formation in wild-type animals. The MIG-15/JNK-1 pathway functions cell autonomously in the mechanosensory neurons, and these kinases localize to presynaptic terminals providing further evidence of a role in synapse development. Loss of MIG-15/JNK-1 signaling also suppresses defects in habituation to repeated mechanical stimuli in rpm-1 mutants, a behavioral deficit that is likely to arise from impaired glutamatergic synapse formation. Interestingly, habituation results are consistent with the MIG-15/JNK-1 pathway functioning as a parallel opposing pathway to RPM-1. These findings indicate the MIG-15/JNK-1 pathway can restrict both glutamatergic synapse formation and short-term learning.
Highlights
Information is relayed throughout the nervous system via chemical synapses, and the process of synapse formation is essential for construction of neural circuitry [1, 2]
Our results have identified a conserved MIG-15/JNK-1 MAPK pathway that restricts formation of glutamatergic, neuron-neuron synapses in the mechanosensory neurons, but does not restrict synapse formation in motor neurons
This could have important implications because synapses made by the mechanosensory neurons are reminiscent of synapses in the mammalian central nervous system, and relatively little is known about the signals that influence central synapse formation in vivo
Summary
Information is relayed throughout the nervous system via chemical synapses, and the process of synapse formation is essential for construction of neural circuitry [1, 2]. Only the mechanosensory neurons form glutamatergic, neuron-neuron synapses that are reminiscent of central synapses. Genetic screens using mechanosensory neurons have revealed several molecules that regulate glutamatergic synapse formation including the intracellular signaling hub Regulator of Presynaptic Morphology 1 (RPM-1) [5], the F-box protein MEC-15 [6], the transcription factor SAM-10 [7], the focal adhesion protein ZYX-1/Zyxin [8], and the microRNA LIN-4 [9]. C. elegans has two PLM mechanosensory neurons, which sense posterior gentle touch [10]. The PLM neurons form electrical synapses and glutamatergic chemical synapses with postsynaptic interneurons [10,11,12]. Initial touch sensation is thought to rely upon both electrical synapses and glutamatergic transmission. Glutamatergic transmission is required for more complex touch-response behaviors, such as habituation to repeated tap and arousal from a sleep-like state called lethargus [13, 14]
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