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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD055380-04
Application #
8075074
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Henken, Deborah B
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2011-05-01
Budget End
2012-04-30
Support Year
4
Fiscal Year
2011
Total Cost
$335,254
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Desbois, Muriel; Cook, Steven J; Emmons, Scott W et al. (2015) Directional Trans-Synaptic Labeling of Specific Neuronal Connections in Live Animals. Genetics 200:697-705
Díaz-Balzac, Carlos A; Lázaro-Peña, María I; Ramos-Ortiz, Gibram A et al. (2015) The Adhesion Molecule KAL-1/anosmin-1 Regulates Neurite Branching through a SAX-7/L1CAM-EGL-15/FGFR Receptor Complex. Cell Rep 11:1377-84
Díaz-Balzac, Carlos A; Lázaro-Peña, María I; Tecle, Eillen et al. (2014) Complex cooperative functions of heparan sulfate proteoglycans shape nervous system development in Caenorhabditis elegans. G3 (Bethesda) 4:1859-70
Salzberg, Yehuda; Ramirez-Suarez, Nelson J; Bülow, Hannes E (2014) The proprotein convertase KPC-1/furin controls branching and self-avoidance of sensory dendrites in Caenorhabditis elegans. PLoS Genet 10:e1004657
Tecle, Eillen; Diaz-Balzac, Carlos A; Bulow, Hannes E (2013) Distinct 3-O-sulfated heparan sulfate modification patterns are required for kal-1-dependent neurite branching in a context-dependent manner in Caenorhabditis elegans. G3 (Bethesda) 3:541-52
Salzberg, Yehuda; Diaz-Balzac, Carlos A; Ramirez-Suarez, Nelson J et al. (2013) Skin-derived cues control arborization of sensory dendrites in Caenorhabditis elegans. Cell 155:308-20
Attreed, Matthew; Desbois, Muriel; van Kuppevelt, Toin H et al. (2012) Direct visualization of specifically modified extracellular glycans in living animals. Nat Methods 9:477-9
Townley, Robert A; Bülow, Hannes E (2011) Genetic analysis of the heparan modification network in Caenorhabditis elegans. J Biol Chem 286:16824-31
Aguirre-Chen, Cristina; Bülow, Hannes E; Kaprielian, Zaven (2011) C. elegans bicd-1, homolog of the Drosophila dynein accessory factor Bicaudal D, regulates the branching of PVD sensory neuron dendrites. Development 138:507-18
Tornberg, Janne; Sykiotis, Gerasimos P; Keefe, Kimberly et al. (2011) Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci U S A 108:11524-9

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