William Wadsworth Professor UMDNJ-RWJMS Department of Pathology R-228 Piscataway. NJ 08854 (732) 235-4144 FAX - 4825 wadswort@umdnj.edu

Extracellular matrix and the guidance of cell migrations in C. elegans

During development. some cells must migrate to distant sites before dividing and differentiating. In the developing nervous system. precise patterns of synaptic connections are formed as pioneering axons migrate to find their correct target regions. Our goal is to understand how axon and cell migrations are guided.

Our research employs the powerful genetic and molecular techniques available to study development and function in the nematode C. elegans. The unc-6 gene is required for guiding dorsal and ventral migrations on the basal surface of the epidermis. This gene encodes a novel laminin-related extracellular matrix protein. A family of vertebrate axon outgrowth-promoting proteins. the netrins. are homologous to UNC-6. The analysis of UNC-6 in the nematode and of the netrins in the developing spinal cord indicate these molecules guide circumferential axon migrations. As a simple hypothesis. UNC-6/netrin is a secreted matrix guidance cue which is tracked by receptors expressed on the surface of migrating cells. This model provides the basis to study structural arrangements and biological properties of the various components which comprise this guidance system. This laboratory is studying the spatial and temporal expression of UNC-6. is studying structure /function relationships using transgenic strains expressing netrin or UNC-6 mutant alleles. and is studying biochemical relationships between UNC-6. netrin. and other extracellular matrix proteins.

Selected Publications

Quinn CC, Wadsworth WG. (2008) Axon guidance: asymmetric signaling orients polarized outgrowth. Trends Cell Biol. 18(12):597-603.

Quinn CC, Pfeil DS, Wadsworth WG. (2008) CED-10/Rac1 mediates axon guidance by regulating the asymmetric distribution of MIG-10/lamellipodin. Curr Biol. 18(11):808-13.

Kulkarni G, Li H, Wadsworth WG. (2008) CLEC-38, a transmembrane protein with C-type lectin-like domains, negatively regulates UNC-40-mediated axon outgrowth and promotes presynaptic development in Caenorhabditis elegans. J Neurosci. 28(17):4541-50.

Li H, Kulkarni G, Wadsworth WG. (2008) RPM-1, a Caenorhabditis elegans protein that functions in presynaptic differentiation, negatively regulates axon outgrowth by controlling SAX-3/robo and UNC-5/UNC5 activity. J Neurosci. 28(14):3595-603.

Quinn CC, Wadsworth WG. (2006) Axon guidance: ephrins at WRK on the midline. Curr Biol. 16(22):R954-5. Review.

Quinn CC. Pfeil DS. Chen E. Stovall EL. Harden MV. Gavin MK. Forrester WC. Ryder EF. Soto MC. Wadsworth WG. (2006) UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/lamellipodin. Curr Biol. ;16(9):845-53.

Kao G. Huang CC. Hedgecock EM. Hall DH. Wadsworth WG. (2006) The role of the laminin beta subunit in laminin heterotrimer assembly and basement membrane function and development in C. elegans. Dev Biol. 290(1):211-9.

Wadsworth WG. (2005) Axon pruning: C. elegans makes the cut. Curr Biol. 15(19):R796-8.

Yurchenco PD. Wadsworth WG. (2004) Assembly and tissue functions of early embryonic laminins and netrins. Curr Opin Cell Biol. 16(5):572-9.

Huang CC. Hall DH. Hedgecock EM. Kao G. Karantza V. Vogel BE. Hutter H. Chisholm AD. Yurchenco PD. Wadsworth WG. (2003) Laminin alpha subunits and their role in C. elegans development. Development. 130(14):3343-58.

Merris M. Wadsworth WG. Khamrai U. Bittman R. Chitwood DJ. Lenard J. (2003) Sterol effects and sites of sterol accumulation in Caenorhabditis elegans: developmental requirement for 4alpha-methyl sterols. J Lipid Res. 44(1):172-81.

Lim YS. Wadsworth WG. (2002) Identification of domains of netrin UNC-6 that mediate attractive and repulsive guidance and responses from cells and growth cones. J Neurosci. 22(16):7080-7.

Wadsworth WG.(2002) Moving around in a worm: netrin UNC-6 and circumferential axon guidance in C. elegans. Trends Neurosci. 25(8):423-9.

Wang Q. Wadsworth WG. (2002) The C domain of netrin UNC-6 silences calcium/calmodulin-dependent protein kinase- and diacylglycerol-dependent axon branching in Caenorhabditis elegans. J Neurosci. 22(6):2274-82.

Kim. S.. and Wadsworth. W. G. (2000). Positioning of longitudinal nerves in C. elegans by nidogen. Science 288:150-154.