kal-1 is the C. elegans homolog of Kal1 the gene responsible in human for X-linked Kallmann Syndrome (KS). KS is an inherited disorder caused by defects of axonal outgrowth in the Olfactory System. The syndrome is genetically heterogeneous and three modes of inheritance have been described: autosomal recessive, autosomal dominant and X-linked. Kal1 encodes a secreted protein involved in olfactory axon guidance. C. elegans is the first animal for which a mutant completely lacking the function of the Kal gene has been produced. The gene is expressed in a subset of C. elegans neurons. The phenotypes presented by loss of function and overexpression mutants indicate that
kal-1 modulates neurite branching in vivo (Rugarli et al., 2002; Bulow et al., 2002). In addition
kal-1 is part of a redundant mechanism by which neurons influence epidermal cells morphogenesis in ventral enclosure, seam cells arrangement and male tail formation. The nematode and human genes are functionally conserved such that the human protein can compensate for the loss of the nematode one (Rugarli et al., 2002). In order to find candidate genes for the autosomal forms of KS, we have looked for interactors and we will show that semaphorin pathway genes act on the same developmental processes in which
kal-1 is involved. With regard to neuronal branching we will describe the role, not studied before, played by
kal-1 in HSN neuron development. The possible mechanism by which
kal-1 acts to affect HSN cell body shape and axon branching will be discussed. In addition, recently identified modifiers of the
kal-1 neurite branching phenotype will be described and could help elucidate the still elusive role of
kal-1 in neuronal development. Finally, we used a modification of the RNA-interference method, recently developed in the lab, to reduce the function of
kal-1 in selected neurons at the posterior end of the animal (Esposito G. et al., 2007). With this approach we were able to determine that the
kal-1 expressing neurons DVA and PDB are responsible for two of the
kal-1 male tail phenotypes, Ray 1 anteriorization and SET cell detachment, but that do not influence other defects (e.g Ray 5 and 6 inversion). At the same time we could also exclude that the
kal-1 expressing neuron, PVW has a role in either Ray 1 anteriorization or SET cell detachment. These results suggest that although KAL-1 is a secreted protein, its range of action is limited in space. This is probably due to the fact that, unlike in other species, CeKAL-1 is anchored to the membrane via GPI.