The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration

Abstract

Three dominant mutations of mec-4, a gene needed for mechanosensation, cause the touch-receptor neurons of Caenorhabditis elegans to degenerate. With deg-1, another C. elegans gene that can mutate to induce neuronal degeneration and that is similar in sequence, mec-4 defines a new gene family. Cross-hybridizing sequences are detectable in other species, raising the possibility that degenerative conditions in other organisms may be caused by mutations in similar genes. All three dominant mec-4 mutations affect the same amino acid. Effects of amino-acid substitutions at this position suggest that steric hindrance may induce the degenerative state.

Touch sensitivity in Caenorhabditis elegans

“…Mutations in either gene produce touch insensitivity [12], and gain-of-function mutations as described above lead to touch receptor neuron degeneration [16,21,30,38]. Both genes are coexpressed in the six touch neurons [38].…”

“…The main pore-forming subunits of this complex are encoded by the mec-4 and mec-10 genes. MEC-4 and MEC-10 are degenerins, a class of ion channels in C. elegans named after the neuronal degeneration phenotype caused by gain-of-function alleles [16,21,38]. Degenerins are part of the degenerin/epithelial sodium channel (DEG/ ENaC) protein superfamily found in invertebrates and vertebrates.…”

“…The second transmembrane domain (TMII) and the sequence preceding it are thought to contribute to the pore of the channel; mutations in these regions cause constitutive channel activity, blockage of the constitutive activity, or changes in ion selectivity [36,37,57]. The mutations that cause constitutive channel activity were first identified as changes in MEC-4, MEC-10, and other C. elegans degenerins that cause neurodegeneration [16,21,38]. Substitutions of large-side chain residues for an alanine in the region preceding TMII cause hyperactivation and toxic influx of ions [21,36,75].…”

“…The mutations that cause constitutive channel activity were first identified as changes in MEC-4, MEC-10, and other C. elegans degenerins that cause neurodegeneration [16,21,38]. Substitutions of large-side chain residues for an alanine in the region preceding TMII cause hyperactivation and toxic influx of ions [21,36,75]. Additional degeneration-causing and gain-of-function mutations have been found affecting the degenerin ERD, suggesting that this region of the extracellular loop gates channel activity [30,84].…”

Electrical activity and behavior in the pharynx of caenorhabditis elegans

“…The use of the laser ablation method to assign behavioral roles to neurons and thus provide a context for characterizing mutations has proven extremely powerful in the genetic dissection of other behaviors in C. elegans (for review see Bargmann, 1993). By the molecular cloning of genes altered by some of these mutations, molecules that function in specific behaviors have been identified and studied (e.g., Driscoll and Chalfie, 1991).…”