A critical but poorly understood aspect of neurobiology is how the integrity and function of an established nervous system is protected throughout life, despite post-embryonic body growth, movement, and the incorporation of new neurons into existing neural circuits. Dedicated mechanisms must be in place to protect the nervous system in spite of these stresses, and a handful of molecules have been identified that maintain the precise organization of neural circuits after their initial establishment (1). SAX-7, the C. elegans ortholog of the L1CAM family of cell adhesion molecules (2 - 4), functions in neurons to maintain the position of neuronal soma and axons (3, 5). Despite their normal initial development, a subset of embryonically developed axons of the ventral nerve cord become defasciculated during the first larval stage in
sax-7 mutant animals, and specific neuronal soma within ganglia become progressively displaced in later larval and adult stages of
sax-7 mutant animals (3 - 6). SAX-7/L1CAM is a transmembrane protein of the immunoglobulin superfamily with roles as a cell adhesion molecule (2 - 4). In vertebrates, L1CAM carries out developmental roles in migration and fasciculation, and in humans, mutations in L1CAM lead to neurodevelopmental disorders. Moreover, L1CAM plays a role in the adult vertebrate brain, as a conditional knock out in the adult mouse brain leads to behavioral deficits (7), highlighting that both C. elegans SAX-7 and vertebrate L1CAM have continued importance in the adult nervous system to promote its integrity and functionality. To elucidate the molecular mechanisms by which SAX-7 functions to maintain the nervous system and identify conserved neuronal protection molecules, we have carried out a forward genetic screen for modifiers of the
sax-7 mutant maintenance phenotype of ASH/ASI soma displacement. We expect that the enhancer and suppressor mutations of this
sax-7 mutant phenotype will define genes that normally function to promote, or to antagonize neuronal maintenance, respectively. From screening 6,000 haploid genomes, we have successfully outcrossed and reisolated 5 suppressors and 2 enhancers of the
sax-7 mutant phenotype. One isolated suppressor,
nema-1, suppresses the
sax-7 ASH/ASI maintenance defects, but not other phenotypes of
sax-7 mutants. We are characterizing these suppressors and enhancers of
sax-7.1) Benard and Hobert , 2009; 2) Chen et al., 2001; 3) Sasakura et al., 2005; 4) Wang et al., 2005; 5) Pocock et al., 2008; 6) Zhou et al., 2008; 7) Law et al., 2003.