Kallmann syndrome is a neurological disorder characterized by various behavioral and neuroanatomical defects. The X-linked form of this disease is caused by mutations in the KAL-1 gene, which codes for a secreted molecule that is expressed in restricted regions of the brain. Its molecular mechanism of action has thus far remained largely elusive. We show here that expression of the Caenorhabditis elegans homolog of KAL-1 in selected sensory and interneuron classes causes a highly penetrant, dosage-dependent, and cell autonomous axon-branching phenotype. In a different cellular context, heterologous C. elegans kal-1 expression causes a highly penetrant axon-misrouting phenotype. The axon-branching and -misrouting activities require different domains of the KAL-1 protein.In a genetic modifier screen we isolated several loci that either suppress or enhance the kal-1-induced axonal defects, one of which codes for an enzyme that modifies specific residues in heparan sulfate proteoglycans, namely heparan-6O-sulfotransferase. We hypothesize that KAL-1 binds by means of a heparan sulfate proteoglycan to its cognate receptor or other extracellular cues to induce axonal branching and axon misrouting. K allmann syndrome is a genetic disease that was first recognized as such in 1944 by Franz Kallmann (1) and is defined as the association of hypogonadotropic hypogonadism and anosmia, i.e., the inability to smell. In addition, affected patients may display a variety of neurological abnormalities, including synkinesia (mirror movement) of the hands, as well as somatic defects such as unilateral renal agenesis (2, 3). Embryological studies suggested a common origin for the anosomic and hypogonadotropic phenotypes (4). During development, the olfactory receptor neurons born in the olfactory primordium project and extend their axons through the cribriform plate into the skull where they establish connections with secondary neurons in the olfactory bulb. Likewise, the neurons that later secrete gonadotropin-releasing hormone (GnRH) are born in the olfactory primordium and migrate along the olfactory tract to their final destination in the hypothalamus. Based on neuropathological studies on a human fetus affected by X chromosome-linked Kallman syndrome (5), it has been suggested that (i) the axons of the olfactory receptor neurons still project toward the forebrain; however, they fail to establish connections with their target cells), and (ii) GnRH-synthesizing neurons fail to reach the hypothalamus, thus disrupting the hypothalamic-pituitary hormonal axis and causing hypogonadotropic hypogonadism.Genetically, Kallmann syndrome is heterogeneous with examples of autosomal recessive, autosomal dominant, as well as X-linked recessive modes of inheritance [see Online Mendelian Inheritance in Man (OMIM) at http:͞͞www.ncbi.nlm.nih.gov͞omim͞]. Although the molecular lesions responsible for the autosomal forms remain elusive, the gene for the X-linked form, named KAL-1, was identified more then 10 years ago (6, 7) and shown to code for a s...

The Caenorhabditis elegans excretory canal is composed of a single elongated and branched cell that is tunneled by an inner lumen of apical character. Loss of the exc-4 gene causes a cystic enlargement of this intracellular tube. exc-4 encodes a member of the chloride intracellular channel (CLIC) family of proteins. EXC-4 protein localizes to various tubular membranes in distinct cell types, including the lumenal membrane of the excretory tubes. A conserved 55-amino acid domain enables EXC-4 translocation from the cytosol to the lumenal membrane. The tubular architecture of this membrane requires EXC-4 for both its formation and maintenance.

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