Formation of such an elaborate structure as the nervous system requires the concerted action of numerous molecules many of which reside in the molecularly complex extracellular matrices (ECMs). Neurons receive and integrate the guidance signals they encounter in the ECMs with specialized receptors and translate them into a directed growth response. Whereas the identity of many guidance molecules has been determined, very little is known about their interactions with the ECM's and how these interactions control their activity. We are investigating how the molecular complexity of ECMs together with the signaling molecules that respond to this complexity define neuronal development. KAL1 is an extracellular neural adhesion molecule that is mutant in Kallmann Syndrome, a hereditary disorder with specific neuronal migration and targeting defects. However, the molecular function of KAL1 and potential interacting partners in neuronal development remains unknown. We are using a genetic approach in C. elegans to study the function of kal-1 (the C. elegans ortholog of KAL1) in nervous system development. In a genetic screen we have identified several loci that interact with kal-1 three of which imply modifications of heparan sulfate, integral polysaccharide components of the ECMs, in kal-1 function. This research will analyze the function of kal-1 in nervous system development, define the interactions of kal-1 with heparan sulfate proteoglycans and identify novel genes that interact with kal-1 and mediate its function in vivo. The study of KAL-1 will give important insights into the intricate relationship between ECM's and KAL-1 function during neuronal development and disease. Importantly, any novel locus that we identify is a candidate gene in molecularly elusive cases of Kallmann Syndrome. Project Narrative: KAL-1 is a cell adhesion molecule of the extracellular space which is mutant in Kallmann Syndrome, a genetic disease with neuronal targeting and migration defects. We are using a genetic approach in C. elegans in order to understand how and with which other genes kal-1 functions during neuronal development and disease.
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