We are interested in understanding the molecular mechanisms underlying the connection specificity between neurons at synapse formation level.  In other words, how do neurons choose their synaptic partners during synaptogenesis?  Can molecules encode target specificity?

Both anatomical and physiological evidences from different experimental systems support the notion that many synapses are selectively formed between specific synaptic partners at certain subcellular compartments (Gupta et al., 2000; Dantzker and Callaway, 2000; Kozloski et al., 2001). Cellular and subcellular target selection is essential for the functionality of neuronal circuits. These “hardwired” neuronal circuits are likely important for innate behaviors or forming the prototype neural substrate that can be further shaped by experience.  It is not yet well understood if molecular mechanisms are the driving force of synaptic specificity and subcellular specificity.  I propose to identify molecules that mediate the recognition between synaptic partners during synaptogenesis and to understand how recognition molecules direct synapse formation.  In the last couple of years, we have analyzed synaptic specificity and synapse formation of a motor neuron, HSNL in C. elegans (Fig.1).  We discovered that a pair of Immunoglobulin Superfamily proteins, SYG-1 and SYG-2, is essential for the synaptic choice of HSNL (Shen and Bargmann, 2003; Shen et al., 2004).  In syg-1 or syg-2 mutants, presynaptic neuron HSNL contacts its normal synaptic partners but fails to form synaptic connections with them.  Instead, ectopic synapses are formed onto abnormal postsynaptic targets.  SYG-1 and SYG-2 both localize to synapses and bind to each other, acting as receptor and ligand.  SYG-1 functions cell autonomously in the presynaptic neuron.  SYG-2 functions in the guidepost cells, a group of epithelial cells that is essential for the correct formation of HSNL synapses (Shen and Bargmann, 2003; Shen et al., 2004).  For the next few years, we will expand this discovery in several different directions:

Direction 1: How do SYG-1 and SYG-2 establish synaptic specificity and assemble synapses?
We hypothesize that SYG-1/SYG-2 interaction both triggers synaptic assembly with normal synaptic partners and inhibits synapse formation with abnormal synaptic partners.  We will use genetic and biochemical means to understand the signaling pathways triggered by the SYG-1/SYG-2 interaction.  We are carrying out forward genetic screens and modifier screens, together with biochemistry experiments. 

Direction 2:  What are the other synaptic specificity molecules in C. elegans?
Our expression analysis suggests that SYG-1 and SYG-2 are only expressed in a subset of neurons and muscles in C. elegans.  Are there other molecules like SYG-1 and SYG-2 that specify synapses in other neurons?  We are labeling synapses with cell specific promoters.  We will perform developmental and genetic analysis on those labeled synapses to understand the specificity mechanisms of other synapses. 

Direction 3: Are the vertebrate homologues of SYG-1 and SYG-2 involved in synaptogenesis ?
SYG-1 and SYG-2 belong to an evolutionarily conserved family of Immunoglobulin like proteins.  NEPH1 and Nephrin are homologues of SYG-1 and SYG-2, respectively.  Both NEPH1 and Nephrin are essential for the formation of slit diaphragm in the kidney.  Mutations in both genes cause congenital nephrotic syndrome.  Both NEPH1 and Nephrin are expressed in the central nervous system.  We propose to study their functions in synapse formation in vertebrate systems.

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