Ph.D. (Molecular and Cellular Pathology) 2000, Stony Brook University, NY
Phone: 202.687.2878
Fax: 202.687.0617
E-mail: ls379@georgetown.edu

Synaptogenesis involves the precise temporal and spatial orchestration of molecule biogenesis and targeting to presynaptic and postsynaptic compartments.  Numerous cell adhesion molecules have been identified that participate in synapse formation.
Dr. Lim's laboratory is focused on nectins. Nectins are Ca2+ independent, immunoglobulin-like adhesion molecules. Mutations in the nectin-1 gene cause cleft lip/palate-ectodermal dysplasia and in some cases mental retardation. Loss of nectin-1 and nectin-3 function in mice exhibits an abnormal mossy fiber trajectory and a reduction in the number of puncta adherentia junctions (PAJs) at synapses between mossy fiber terminals and dendrites of the CA3 pyramidal cells.  These data suggest that nectin plays an important role in synaptogenesis.
We hypothesize that nectin-1 undergoes a regulated multi-step set of endoproteolytic cleavage events by several sheddases in an activity-dependent manner and that these events regulate synaptogenesis and contribute to synaptic plasticity. We postulate that both the ectodomain and intracellular domains each participate uniquely in modulating synaptic structure and likely function. To test this hypothesis, we have identified the two enzymes that cleave the ectodomain and intracellular domain of nectin-1 and have also identified their cleavage products. We are currently investigating the mechanism and role of these cleavage events and possible roles of the cleavage products in synaptogenesis. We would like to investigate how synaptogenesis is affected by the absence of nectin cleavage products in necin-1 and nectin-3 KO mice. We currently are trying to identify novel components of the nectin multiprotein complexes at synapses using two strategies: affinity chromatography followed by high-sensitivity mass spectrometry and yeast two-hybrid screens.

Publications:

1. Lim, S.T., Airavaara, M. and Harvey, B.K. (2009) Viral vectors for neurotrophic factor delivery: A gene therapy approach for neurodegenerative diseases of the CNS. Pharmacol. Research, In Press.
2. Yan, L., Lim, S.T., Hoffman, D., Aspenstrom, R., Federoff, H., and Rempe, D.A. (2009) HUMMR, a hypoxia and HIF-1alpha inducible protein, alters mitochrondrial distribution and transport. J Cell Biol 185 (6): 1065-1081.
3. Chiu, Y., Bowers, W.J., Lim, S.T., Ryan, D. A., and Federoff, H.J. (2009) Effects of HSV amplicon transduction on murine dendritic cell. Human Gene Therapy 20 (5): 442-452.
4. Lim, S.T., Lim, K-C., Giuliano, R.E., and Federoff, H.J. (2008) The Temporal and Spatial Localization of Nectin-1 and l-Afadin during Synaptogenesis in Hippocampal Neurons.  J Comp Neurol. 507 (2): 1228-1244.
5. Lim, K-C., Tyler, C. M., Lim, S.T., Giuliano, R.E., and Federoff, H.J. (2007) Proteolytic Processing of ProNGF is Necessary for Mature NGF Regulated Secretion from Neurons. Biochem Biophys Res Commun 361(3):599-604.
6. Lim, K-C, Lim, S.T., and Federoff, H.J. (2003) Neurotrophin secretory pathways and synaptic plasticity.  Neurobio. 24:1135-1145.
7. Antonucci, D.E., Lim, S.T., Vassanelli, S., and Trimmer, J.S. (2001) Dynamic localization and clustering of dendritic Kv2.1 voltage-dependent potassium channels in developing hippocampal neurons.  Neurosci 108(1):69-81.
8. McCarthy, J.B., Lim, S.T., Elkind, N.B., Trimmer, J.S., Duvoisin, R.M., Rodriguez-Boulan, E., and Caplan, J.M. (2001) The C-terminal tail of the metabotropic glutamate receptor subtype 7 is necessary but not sufficient for cell surface delivery and polarized targeting in neurons and epithelia.  J Biol Chem 23;276(12):9133-9140.
9. Lim, S.T., Antonucci, D.E., Scannevin, R.H., and Trimmer, J.S. (2000) A novel targeting signal for Proximal clustering of the Kv2.1+ channel in hippocampal neurons.  Neuron 25:385-397.
10. Ovalle, R., Lim, S.T., Holder, B., Jue, C.K., Moore, C.W., and Lipke, P.N. (1998) A spheroplast rate assay for determination of cell wall integrity in yeast.  Yeast 14:1159-1166.
11. Lim, S.T., Jue, C.K., Moore, C.W., and Lipke, P.N. (1995) Oxidative cell wall damage mediated by Bleomycin-Fe(ll) in Sacharromyces cerevisiae. J Bact 177:3534-3539.
12. Beaudouin, R., Lim, S.T., Steide, J.A., Powell, M., Mckoy, J., Pramanik, A.J., Johnson, E., Moore, C.W., and Lipke, P.N. (1993). Bleomycin affects cell wall anchorage of mannoproteins in Saccharomyces cerevisiae.  Antimicro Agents Chemother 37:1264-1269.