Heparan sulfate proteoglycan-dependent induction of axon branching and axon misrouting by the Kallmann syndrome gene kal-1.
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.
Bülow
Hannes E
HE
Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.
Berry
Katherine L
KL
Topper
Liat H
LH
Peles
Elior
E
Hobert
Oliver
O
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002460:Cell Line; D003360:Cosmids; D004247:DNA / Q000378:metabolism; D004330:Drosophila; D016326:Extracellular Matrix Proteins; D017930:Genes, Reporter; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D017436:Kallmann Syndrome / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism
C076266:ANOS1 protein, human; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D019812:Heparan Sulfate Proteoglycans; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D004247:DNA