1. Establishment of a molecular genetic program for the generation of GABAergic motor neurons (type-D neurons)

These neurons control the locomotion pattern of the worm. When they are defective, the animals hypercontract body muscles, resulting in a phenotype nicknamed "shrinker." We have characterized several genes, unc-30, unc-25 and unc-47 (unc, uncoordinated), all of which cause a shrinker phenotype when mutated. unc-30 encodes a homeodomain protein and is both necessary and sufficient for specifying aspects of the terminal differentiation of the D neurons (6). unc-25 encodes the GABA biosynthetic enzyme glutamic acid decarboxylase (2). unc-47 encodes the GABA vesicular transporter. We have shown that unc-30 controls the GABAergic property of these type D neurons by regulating the expression of both unc-25 and unc-47 at the transcriptional level (3). We are using a variety of molecular genetic methods to identify additional genes regulated by unc-30 to understand how these D neurons acquire other properties.

2. Identification of the molecular components in the presynaptic termini

Although much progress has been made in understanding neurotransmitter release, relatively little is known about how a synaptic terminus is built architecturally. We use a GFP marker to label the presynaptic regions of the D neurons. From a large scale genetic screen, we isolated more than a dozen genes that, when mutated, disrupt the morphology of the presynaptic termini. We call these genes syd for synapse defective. syd-1 and syd-3 encode proteins that may regulate the formation of specialized cytoskeleton at the synaptic termini through a GTPase signaling pathway (7); syd-2 controls the size of active zone by regulating receptor tyrosine phosphatases (4). We are carrying out genetic and biochemical experiments to investigate the signaling pathway of the syd genes.

3. Characterization of the developmental remodeling of DD motorneurons

An intriguing feature of the DD neurons is that they remodel their synaptic connections during development. This remodeling is unusual because it involves a complete reversal of information flow without dramatic changes in neuronal morphology. We are using a variety of markers to visualize this remodeling process in vivo. We have found that the timing of the remodeling is under the control of a nuclear protein, LIN-14 (1). We are particularly interested in exploring this phenomenon in the hope that our analysis will shed light on other types of synaptic plasticity that are related to growth, aging, learning and memory.

Selected Publications

1. Hallam, S. J., and Jin, Y. (1998) lin-14 regulates synaptic remodeling in Caenorhabditis elegans. Nature 395: 78-82.

 

2. Jin, Y., Jorgensen, E., Hartweig, E. and H. R. Horvitz (1998) The C. elegans gene unc-25 encodes gluatmic acid decarboxylase and is required for synaptic transmission but not synaptic development. J. Neurosci. 19(2):539-548.

 

3. Eastman C, Horvitz HR, Jin Y. (1999) Coordinated transcriptional regulation of the unc-25 glutamic acid decarboxylase and the unc-47 GABA vesicular transporter by the Caenorhabditis elegans UNC-30 homeodomain protein. J Neurosci. 19(15):6225-34 .

 

4. Zhen, M., and Jin, Y.(1999). The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 401(6751):371-5.

 

5. Jorgensen, E.M., Hartwieg,E., Schuske,K., Nonet, M., Jin, Y., and Horvitz, H. R. (1995) Defective recycling of synaptic vesicles in synaptotagmin mutants of C. elegans. Nature 378: 196-199.

 

6. Jin, Y., Hoskins, R., and Horvitz, H. R. (1994). Control of type-D GABAergic neuron differentiation by C. elegans unc-30 homeodomain protein. Nature 372: 780-783.

 

7. Zhen, M., Huang, X., Bamber, B., and Jin, Y. (2000). Regulation of presynaptic terminal organization by C. elegans RPM-1, a putative guanine nucleotide exchanger with a RING-H2 finger domain. Neuron 26:331-343.

 

8. Hallam S, Singer E, Waring D, Jin Y. (2000). The C. elegans NeuroD homolog cnd-1 functions in multiple aspects of motor neuron fate specification. Development127(19):4239-52.

 

9. Joby J. Westmoreland, Jason McEwen, Billie A. Moore, Yishi Jin, and Brian G. Condie. (2001). Conserved Function of Caenorhabditis elegans UNC-30 and Mouse Pitx2 in Controlling
GABAergic Neuron Differentiation. The Journal of Neuroscience 21(17):6810-6819.

10. Crump, J.G., Zhen, M., Jin, Y., and Bargmann, C.I. (2001). The SAD-1 kinase regulates presynaptic vesicle clustering in C. elegans. Neuron 29:115-129.

11. Byrd DT, Kawasaki M, Walcoff M, Hisamoto N, Matsumoto K, and Jin Y. (2001). UNC-16, a JNK-Signaling Scaffold Protein Regulates Vesicle Transport in C. elegans. Neuron 32:787-800.

12. Jin Y. (2002). Synaptogenesis: insights from worm and fly. Curr Opin Neurobiol 12(1):71-9.

13. Baran R and Jin Y. (2002). Getting a GRIP on liprins. Neuron 34(1):1-2.

14. Huang X, Cheng HJ, Tessier-Lavigne M, and Jin Y. (2002). MAX-1, a novel PH/MyTH4/FERM domain cytoplasmic protein implicated in netrin-mediated axon repulsion. Neuron 34(4):563-76.

15. Hallam SJ, Goncharov A, McEwen J, Baran R, Jin Y. (2002). SYD-1, a presynaptic protein with PDZ, C2 and rhoGAP-like domains, specifies axon identity in C. elegans. Nat Neurosci. 5(11):1137-46.

16. Ackley BD, Kang SH, Crew JR, Suh C, Jin Y, Kramer JM. (2003). The basement membrane components nidogen and type XVIII collagen regulate organization of neuromuscular junctions in Caenorhabditis elegans. J Neurosci. 23(9):3577-87.

17. Huang X, Huang P, Robinson MK, Stern MJ, Jin Y. (2003). UNC-71, a disintegrin and metalloprotease (ADAM) protein, regulates motor axon guidance and sex myoblast migration in C. elegans. Development 130(14):3147-3161.