Cis-regulatory Mutations in the Caenorhabditis elegans Homeobox Gene Locus cog-1 Affect Neuronal Development

• Published in: Genetics (Austin) 2009-04, Vol.181 (4), p.1679-1686
• Main Authors: O'Meara, M. Maggie, Bigelow, Henry, Flibotte, Stephane, Etchberger, John F, Moerman, Donald G, Hobert, Oliver
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Binding sites; Caenorhabditis elegans - genetics; Caenorhabditis elegans Proteins - genetics; Cell Differentiation - genetics; Genes, Homeobox; Genetics; Genotype & phenotype; Homeodomain Proteins - genetics; Models, Biological; Molecular Sequence Data; Mutagenesis; Mutation; Mutation - physiology; Neurogenesis - genetics; Neurons - physiology; Proteins; Regulatory Elements, Transcriptional - genetics; Reverse engineering; Sequence Homology, Nucleic Acid; Transcription Factors - genetics
• ISSN: 0016-6731; 1943-2631; 1943-2631
• DOI: 10.1534/genetics.108.097832

We apply here comparative genome hybridization as a novel tool to identify the molecular lesion in two Caenorhabditis elegans mutant strains that affect a neuronal cell fate decision. The phenotype of the mutant strains resembles those of the loss-of-function alleles of the cog-1 homeobox gene, an inducer of the fate of the gustatory neuron ASER. We find that both lesions map to the cis-regulatory control region of cog-1 and affect a phylogenetically conserved binding site for the C2H2 zinc-finger transcription factor CHE-1, a previously known regulator of cog-1 expression in ASER. Identification of this CHE-1-binding site as a critical regulator of cog-1 expression in the ASER in vivo represents one of the rare demonstrations of the in vivo relevance of an experimentally determined or predicted transcription-factor-binding site. Aside from the mutationally defined CHE-1-binding site, cog-1 contains a second, functional CHE-1-binding site, which in isolation is sufficient to drive reporter gene expression in the ASER but in an in vivo context is apparently insufficient for promoting appropriate ASER expression. The cis-regulatory control regions of other ASE-expressed genes also contain ASE motifs that can promote ASE neuron expression when isolated from their genomic context, but appear to depend on multiple ASE motifs in their normal genomic context. The multiplicity of cis-regulatory elements may ensure the robustness of gene expression.