The molecular mechanisms through which cells and neuronal growth cones migrate, adhere to the substrate and find their targets are varied, appear to often work in redundant pathways and appear to be conserved in evolution. Many molecules involved in these processes still need to be discovered, especially the components of the extra cellular matrix that play a role in the final steps of morphogenesis. We have focused our study on
kal-1, the C. elegans homolog of the X-linked Kallmann Syndrome gene. KS is an inherited disorder defined by the association of anosmia and hypogonadism, owing to impaired targeting and migration of olfactory axons and gonadotropin-releasing hormone secreting neurons. The gene responsible for the X-linked form of KS, Kal1, encodes a secreted protein which has been proposed to be involved in some aspects of olfactory axon guidance. We have identified the C. elegans homolog,
kal-1, and have documented its function in the nematode studying its expression pattern and using loss of function and overexpression mutants. We have shown that
kal-1 is part of a redundant mechanism by which neurons influence migration and adhesion of epidermal cells morphogenesis in ventral enclosure, seam cells arrangement and male tail formation. We have also shown that
kal-1 affects neurite outgrowth in vivo by modulating branching. In order to comprehend the still elusive role played by
kal-1 in the ECM and to find candidate genes for the autosomal forms of KS, we have looked for interactors. We have choosen mutants in genes which represent good candidates on the basis either of vertebrate studies and/or of the similarity of the phenotypes they generate in the worm. Among these genes we observed interesting results with the semaphorins. The semaphorins are a family of secreted proteins mainly involved in axon guidance in vertebrates. In C. elegans mutants show minor defects in the nervous system, but alterations in cell migration and adhesion with a set of phenotypes similar to that of
kal-1 mutants. The study of epithelial morphogenesis in various genetic combination has indeed shown a complex but specific genetic interaction between
kal-1 and both type of semaphorins. The fact that these multi-domain proteins are secreted and are interacting in the extracellular space and on the cell surface with many other molecules complicates the interpretation of the mechanisms involved. Its noteworthy that the expression of semaphorin genes is widespread and includes epidermal cells affected in
kal-1 mutants, while
kal-1 is produced only by underlying neurons, suggesting that KAL-1 may play a role as modulator of the semaphorins action.