Patterning events in the nervous system occur along the anterior/posterior, dorsal/ventral and left/right (L/R) axes to create the cellular diversity that characterizes most nervous systems. The molecular mechanisms of differential pattern formation along the left/right axis in the nervous system are least understood. The nervous system of C. elegans displays several examples of L/R asymmetry, one being the unbiased antisymmetrical expression of the putative odorant receptor gene,
str-2, displayed by the two bilaterally symmetric AWC odorsensory neurons, AWCL and AWCR (Troemel et al., Cell 1999), and another being the biased, directionally asymmetric expression of several guanyl cylase genes,
gcy-5,
gcy-6, and
gcy-7, displayed by the two otherwise bilaterally symmetric ASE taste receptor neurons, ASEL and ASER (Yu et al., PNAS 1997; Hobert et al., Development 1999; Hobert et al., Nat Rev Neurosci 2002). The functional significance of the L/R separation of odorsensory and chemosensory receptor distributions appears to be to increase the sensory capacities of the worm (Pierce-Shimomura et al., Nature 2001; Wes and Bargmann, Nature 2001). In order to elucidate the molecular mechanisms required to restrict expression of genes in an asymmetric manner to just one of the two ASE neurons, we have undertaken a genetic screen to uncover mutants that show symmetrization of normally asymmetric ASE(L/R) features. Analysis of these mutants (see abstract by Johnston, Jr. et al.) revealed that several symmetrically and asymmetrically expressed transcription factors, including the Nkx-6-type homeobox gene
cog-1, the Zn-finger transcription factor
die-1, the otx-type homeobox gene
ceh-36 and the LIM homeobox gene
lim-6 as well as the putative transcriptional cofactors
unc-37/Groucho and the bromodomain-containing
lin-49 gene are required to restrict
gcy-5 gene expression to ASER and
gcy-7 gene expression to ASEL. Genetic interaction tests suggest specific interaction patterns of these transcription factors. We have also shown that both left and right side-specific features of ASE(L/R) as well as bilaterally symmetric features of ASE(L/R) require the
che-1 gene for correct expression. Our results suggest that starting from a symmetric ground state, which requires non-side-specific subtype-specification factors such as
che-1, a complex series of transcriptional regulatory interactions leads to a diversification of L/R specific features of the ASE neuron class which ultimately serves to increase its functional capacities.