C. elegans as a Genetic Model for Hydrocephalus
Hydrocephalus is a disease characterized by the abnormal accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain. This abnormal fluid accumulation puts pressure on the surrounding brain tissue, resulting in secondary cerebral abnormalities, including seizures and intellectual or developmental disabilities. One of the most well studied proteins linked to congenital hydrocephalus is the mammalian L1 cell adhesion molecule (L1CAM). The model system Caenorhabditis elegans has a single canonical L1CAM protein, encoded by the Sax-7 gene. Sax-7 has many genetic interactors, such as proteins that are part of the Ras-ERK signaling pathway, responsible for many cellular processes including fluid regulation. It is suggested that Sax-7 function antagonizes ERK activation and/or signaling. Thus animals that have impaired Sax-7 function and elevated Ras-ERK signaling fill with fluid, synonymous with the process of hydrocephalus. Sax-7 works with the cytoplasmic protein grdn-1 to anchor dendrites to the nose of the worm. Given the similar role of these two proteins, it is possible that animals with impaired grdn-1 function and elevated Ras-ERK signaling would also fill with fluid. Additionally, L1CAM proteins have been found to bind RanBPM proteins, which function in a degradation complex to degrade proteins in the Ras-ERK signaling pathway. The C. elegans RanBPM protein is encoded by the Gid-1 gene. Given that Gid-1 may interact with the C. elegans L1CAM protein, Sax-7, it is possible that Gid-1 may function in the same pathway or in a parallel pathway with Sax-7 to regulate fluid filling in the worms. It was hypothesized that both Grdn-1 and Gid-1 function in the same pathway as Sax-7 to regulate fluid filling in C. elegans. Double mutant Grdn-1 and Ras-ERK signaling worms and triple mutant Sax-7, Gid-1, and Ras-ERK signaling worms were generated and fluid filling phenotypes were quantified for the strains. There appeared to be no significant differences between the fluid filling observed in Grdn-1 double mutant worms compared to single mutant worms, suggesting that Grdn-1 does not function in relation to Sax-7. Additionally, Grdn-1 mutant animals exhibited different phenotypes compared to the Sax-7;let-60 animals further suggesting that Grdn-1 does not function in fluid regulation in C. elegans. Further studies are needed to elucidate the exact mechanisms by which Gid-1 functions to promote fluid filling in C. elegans and the links to hydrocephalus.