The Jin lab research focuses on the molecular genetic mechanisms underlying the development and function of the nervous system, as well as those underlying adult axon regeneration. Our work is carried out in the nematode Caenorhabditis elegans, whose entre cell lineage and connectome are known. The transparency, defined anatomy, and rapid life cycle of this organism greatly facilitate the molecular genetic dissection in living animals at the subcellular resolution. Through forward genetic screening in combination with multi-layered molecular and cellular manipulations, we are discovering key molecules that play conserved roles in axon pathfinding, synapse formation and function, and axon regeneration. Our ultimate goal is to connect the studies of basic mechanisms to the understanding of human neurological disorders and neuronal repair.
How is a neuron guided to their partner? Neurons rely on specialized subcellular structures, called growth cones, to be guided to their targets. Our previous work has contributed to the understanding of the conserved netrin signaling pathway. In our recent work, we have uncovered a surprising role of a novel protein EBAX-1 that functions in protein quality control of the Robo receptor (Wang et al., Neuron, 2013). Interestingly, a human disorder is associated with mutations in Robo3 receptor. Our results suggest that some of these mutations may cause poor activity of Robo3.
How does a neuron form synapses with its partners? Synapses are the means that neurons use to communicate with others. At the presynaptic terminal, neurons develop elaborate subcellular structures to facilitate the accumulation and release of synaptic vesicles. We use fluorescent markers to label different components of presynaptic terminals in vivo. In combination with forward genetic screening, we have identified new signaling molecules that function through GTPases, endosomes, and ubiquitin-mediated protein degradation to specify distinct spatial domains of the presynaptic terminals (Nakata et al., Cell 2005; Grill et al., Neuron, 2007; Yan et al., Cell 2009). Our recent work has revealed unexpected roles of mRNA processing in synaptogenesis (Van Epps et al., Development, 2010). Our on-going studies combine genomics with genetics to uncover the specific pathways linking synapses to nuclear regulation.
How do neuronal circuit operate to control movement? A central feature of C. elegans movement, namely locomotion, is a balanced excitation and inhibition to body muscles. The locomotion circuit consists cholinergic and GABAergic motor neurons that coordinately control muscle activity. We are examining the roles of neuronal ACh receptors in modulating the excitation state of these two types of neurons (Jospin et al., PLoSBiol, 2009). Our analysis of genetic mutations has also led us to establish a novel model for epilepsy (Stawicki et al., Current Biology, 2011; Stawicki et al., PLoSGenetics, 2013). We have also developed innovative optogenetic tools to perturb neural circuit in situ (Qi et al., PNAS 2012).
How do adult axons regenerate? Understanding how neural circuit forms during normal development has direct implications to the process of how injured neurons repair and regain function in adult animals. Using an ultrafast laser-based microsurgery procedure to perform axotomy in C. elegans neurons (Yanik et al., Nature 2004), we have identified numerous pathways regulating the rate and accuracy of adult axon regeneration. Our current studies focus on the role of the conserved MAPKKK DLK-1 in axon regeneration (Yan et al., Cell 2009; Yan and Jin, Neuron, 2012). By advancing our knowledge of intrinsic signaling pathways, we hope to develop new strategies to enhance regrowth ability of injured axons.
Wang, Z., Hou, Y., Guo, X., van der Voet, M., Boxem, M., Dixon, J. E., and Jin, Y. (2013) The EBAX-type Cullin-RING E3 ligase and Hsp90 guard the protein quality of the SAX-3/Robo receptor in developing neurons. Neuron, 79: 903-16.
Stawicki, T. M., Takayanagi-Kiya, S. Zhou, K., and Jin, Y. (2013) Neuropeptides Function to Dampen Severity of Epileptic-Like Convulsions in C. elegans. PLoS Genetics, 9 (5):e1003472.
Yan, D., and Jin, Y. (2012). The DLK-1 kinase is activated by calcium-mediated dissociation from an inhibitory isoform in C. elegans neuronal development and axon regeneration. Neuron, 76:534-48.
Qi, B. Y., Garren, E., Shu, X., Tsien, R. Y., and Jin, Y. (2012). Photo-inducible cell ablation in C. elegans using the genetically encoded singlet oxygen generating protein miniSOG. Proc Natl Acad Sci U S A. 109:7499-504
Stawicki, T.M., Zhou, K., Yochem J., Chen, L., and Jin, Y. (2011). TRPM channels modulate epileptic-like convulsions via systemic ion homeostasis. Current Biology 21(10):883-888.
Van Epps, H., Dai, Y., Qi, Y. B., Goncharov, A., and Jin, Y. (2010). Nuclear pre-mRNA 3’ end cleavage and polyadenylation regulate synapse and axon development in C. elegans. Development, 137:2237-2250.
Yan, D., Wu, Z., Chisholm, A. D., and Jin, Y. (2009). The DLK-1 kinase promotes mRNA stability and local translation in synapses and axon regeneration. Cell 138:1005-1018.
Jospin, M., Stawicki, T., Qi, Y.B., Boulin, T., Horvitz, H. R., Bessereau, J. L., Jorgensen, E., and Jin, Y. (2009). An neuronal acetylcholine receptor regulates C. elegans locomotion. PLoS Biol. Dec;7(12):e1000265.
Nakata, K., Abrams, B., Grill, B., Goncharov, A., Huang, X., Chisholm, A. D., and Jin, Y. (2005). Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell 120:407-420.
Yanik, M. F., Cinar, H., Cinar, H. N., Chisholm, A. D., Jin, Y., and Ben-Yakar, A. (2004). Neurosurgery: functional regeneration after laser axotomy. Nature 432:822.
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.
Zhen, M., and Jin, Y. 1999. The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 401:371-375.
Hallam, S.J., and Jin, Y. 1998 lin-14 regulates the timing of synaptic remodelling in Caenorhabditis elegans. Nature 395:78-82.
Yan, D., Noma, K., and Jin, Y. (2012) Expanding views of presynaptic terminals: new findings from Caenorhabditis elegans. Curr Opin Neurobiol. 22(3):431-7.
Wang, Z., and Jin, Y. (2010). Genetic analysis of axon regeneration. Curr. Opin. Neurobiol. 21:1-8.
Jin, Y. and Garner, C. C. (2008). Molecular mechanisms of presynaptic differentiation. Annual Review of Cell and Development 24:237-262.
Dr. Jin received her B.S. degree from Peking University, China, and her Ph.D. from the University of California, Berkeley. She completed her postdoctoral training at MIT.