Inositol monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans

Abstract

Although recent studies have provided significant molecular insights into the establishment of neuronal polarity in vitro, evidence is lacking on the corresponding phenomena in vivo, including correct localization of synaptic components and the importance of this process for function of the nervous system as a whole. RIA interneurons act as a pivotal component of the neural circuit for thermotaxis behavior in the nematode Caenorhabditis elegans and provide a suitable model to investigate these issues, having a neurite clearly divided into pre-and post-synaptic regions. In a screen for thermotaxis mutants, we identified the gene ttx-7, which encodes myo-inositol monophosphatase (IMPase), an inositol-producing enzyme regarded as a bipolar disorder-relevant molecule for its lithium sensitivity. Here we show that mutations in ttx-7 cause defects in thermotaxis behavior and localization of synaptic proteins in RIA neurons in vivo. Both behavioral and localization defects in ttx-7 mutants were rescued by expression of IMPase in adults and by inositol application, and the same defects were mimicked by lithium treatment in wild-type animals. These results suggest that IMPase is required in central interneurons of the mature nervous system for correct localization of synaptic components and thus for normal behavior.[Keywords: C. elegans; thermotaxis behavior; protein localization; synapse; myo-inositol monophosphatase; lithium] Supplemental material is available at http://www.genesdev.org. Received April 19, 2006; revised version accepted October 23, 2006. Neurons are the most highly polarized animal cell type and are composed of several subcellular compartments, including axons, dendrites, and cell bodies, each of which has its own molecular and physiological characteristics. How these polarized compartments are established has been extensively investigated using cultured hippocampal neurons as a model system (Dotti and Banker 1987;Dotti et al. 1988). Recent studies have demonstrated that GSK-3␤ and small GTPase-mediated signaling pathways are critical in assigning axonal fate to the immature neurite in hippocampal neurons (Arimura and Kaibuchi 2005;Jiang et al. 2005). The established axonal compartment is physically separated from the cell body by a molecular diffusional barrier, which is at least partly responsible for maintaining the distinct character of these two compartments (Nakada et al. 2003). However, it remains to be determined whether these mechanisms are common to all neuronal types or other mechanisms exist as well. Furthermore, to understand the physiological importance of polarization and consequent subcellular heterogeneity such as localization of synaptic proteins, it is essential to evaluate how these subcellular phenomena in vivo correlate with the function of neurons and the nervous system as a whole.The nematode Caenorhabditis elegans has a simple nervous system that consists of 302 neurons, the synaptic connectivity of which has been described in its entirety by electron microscopy (White et al...

Parallel Use of Two Behavioral Mechanisms for Chemotaxis inCaenorhabditis elegans

“…These neurons receive synaptic inputs from AIY and AIZ neurons and densely innervate head motor neurons SMD and RMD. Laser ablation of RIA neurons and a mutation that impairs the function of these neurons cause athermotactic behavior (Mori and Ohshima, 1995;Tanizawa et al, 2006). However, killing RIA neurons had absolutely no effect on chemotaxis.…”

UNC-4 antagonizes Wnt signaling to regulate synaptic choice in the C. elegans motor circuit

“…8B). Although lithiumdependent inhibition of other targets in C. elegans (Tanizawa et al, 2006) could potentially impede locomotion, this LiCl-induced Unc-4 phenotype is attenuated in a ceh-12 null mutant (Fig. 8B).…”

Microfluidic Platform for Analyzing the Thermotaxis of C. elegans in a Linear Temperature Gradient

“…The ttx-7(nj50) worms showed random distribution in the temperature gradient regardless of the cultivation temperature. 32 According to this result, the ttx-7(nj50) should be distributed evenly in the channel, but ttx-7(nj50) showed a thermophilic response in this study. The main differences in this study are the relatively steeper temperature gradients and the microscale platform.…”

“…Since the inositol is an essential molecule in the RIA neuron, the interneuron that plays a major role in thermotaxis, the ttx-7(nj50) mutant also represents random movements in a temperature gradient. 32 Thus, these two mutants were selected to compare with wild-type worms, to demonstrate the functionality of our platform.…”

“…In previous studies, two mutants, tax-4(p678) and ttx-7(nj50), were reported to represent abnormal thermotaxis. 31,32 Briefly, tax-4(p678) is defective in the tax-4 gene that encodes a cyclic nucleotidegated channel. This channel plays a major role in AFD, the main neuron for thermotaxis.…”