Genetic screens identified several genes that regulate AWC asymmetry. Loss-of-function or reduction-of-function mutations in a calcium-regulated signaling pathway, including a voltage-gated calcium channel (UNC-2, EGL-19, UNC-36), the calcium/ calmodulin-dependent protein kinase II (CaMKII) UNC-43, 

INTRODUCTION The left and right sides of the central nervous system display anatomical, molecular and functional asymmetries throughout the animal kingdom. Functional lateralization in the brain is theorized to increase cognitive performance and social behaviors, as reduced and reverse anatomical brain asymmetry has been linked to a variety of neurodevelopmental disorders (Taylor et al., 2010). However, the mechanisms underlying lateralization of the developing nervous system remain poorly understood. Like the vertebrate central nervous system, the C. elegans nervous system displays molecular and functional asymmetries (Hobert, 2006; Hobert et al., 2002; Sagasti et al., 2001; Taylor et al., 2010). In both ASE taste neurons and AWC olfactory neurons, the left and right neurons of a pair have different patterns of gene expression and respond to different sets of chemicals (PierceShimomura et al., 2001; Troemel et al., 1999; Wes and Bargmann, 2001; Yu et al., 1997). However, the mechanisms that specify ASE and AWC asymmetries are completely distinct. The ASE neurons develop a stereotyped asymmetry early in embryogenesis, whereas the AWC neurons develop stochastic asymmetry late in embryogenesis (Chuang and Bargmann, 2005; Poole and Hobert, 2006). None of the identified ASE asymmetry genes affects AWC asymmetry and, conversely, AWC asymmetry genes do not affect ASE asymmetry (Chang et al., 2003; Koga and Ohshima, 2004; Lanjuin et al., 2003; Lesch et al., 2009). In wild-type animals, the reporter gene str-2p::GFP is expressed in only one of the two AWC neurons, and never in both (Fig. 1A). The two AWC neurons are described as AWCON, which expresses str-2p::GFP, and AWCOFF, which does not. The expression of str2p::GFP in AWC is random: 50% of the animals in a population express str-2 in the left AWC neuron, whereas the other 50% express str-2 in the right AWC. Genetic studies and cell killing experiments suggest that AWCOFF is the default state and asymmetric expression of str-2 requires an interaction between the two AWC neurons (Troemel et al., 1999). Genetic screens identified several genes that regulate AWC asymmetry. Loss-of-function or reduction-of-function mutations in a calcium-regulated signaling pathway, including a voltage-gated calcium channel (UNC-2, EGL-19, UNC-36), the calcium/ calmodulin-dependent protein kinase II (CaMKII) UNC-43, the Tollinterleukin 1 repeat protein TIR-1/SARM, the mitogen-activated protein kinase kinase kinase (MAPKKK) NSY-1/ASK1 and the MAPKK SEK-1 kinase cascade, lead to animals with two AWCON (Fig. 1C; 2AWCON phenotype) and no AWCOFF cells. These results suggest that these genes normally promote the default AWCOFF identity (Bauer Huang et al., 2007; Chuang and Bargmann, 2005; Sagasti et al., 2001; Tanaka-Hino et al., 2002; Troemel et al., 1999). An innexin gap junction protein, encoded by nsy-5, and a claudinlike protein, encoded by nsy-4, function in parallel to inhibit the downstream calcium-regulated signaling pathway in the neuron that acquires the AWCON identity (Chuang et al., 2007; VanHoven et al., 2006). When the activity of nsy-4 or nsy-5 is reduced or lost, mutant animals fail to induce the AWCON cell, leading to the formation of Development 138, 3509-3518 (2011) doi:10.1242/dev.069740 © 2011. Published by The Company of Biologists Ltd