Yishi Jin

Research

The Jin lab research focuses on the molecular genetic mechanisms underlying the development and function of the nervous system using the nematode Caenorhabditis elegans. The transparency, defined anatomy, and rapid life cycle of this organism greatly facilitate our studies at the subcellular resolution. Moreover, the entre cell lineage and connectome are known, enabling functional understanding at deep levels. Through forward genetic screening in combination with multi-layered molecular and cellular manipulations, we are discovering key molecules that play conserved roles in synapse formation, maintenance, and function, as well as those underlying adult axon regeneration. Our ultimate goal is to connect the studies of basic mechanisms to the understanding of human neurological disorders and neuronal repair.

How do neurons form synapses with their partners? Synapses are unique structures that neurons use to communicate with others. At the presynaptic terminal, neurons develop elaborate subcellular organizations to facilitate the accumulation of synaptic vesicles and their release (Kittelmann et al., 2013). We label different components of presynaptic terminals in vivo using fluorescent markers. Through forward genetic screening, we have identified multiple signaling pathways that involve conserved scaffolding proteins, MAP kinases, GTPases, and ubiquitin-mediated protein degradation to specify spatial domains of the presynaptic terminals (Nakata et al., Cell 2005; Grill et al., Neuron, 2007; Yan et al., Cell 2009; Kittelmann et al ., 2013). Synapses also undergo remodeling as animals grow. Our recent studies have elucidated roles of dynamic microtubule cytoskeleton in synaptic remodeling (Kurup et al., Current Biology, 2015). Furthermore, combining genomics with genetics, we have discovered unexpected pathways linking synapse development to nuclear pre-mRNA regulation (Van Epps et al., Development, 2010; Chen et al., Genes and Development, 2015).

How do neural circuits operate to control movement? C. elegans movement, namely locomotion, depends on balanced excitation and inhibition to body muscles. The locomotion circuit consists excitatory cholinergic and inhibitory GABAergic motor neurons. We have examined 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 also led us to establish a novel model for epilepsy (Stawicki et al., Current Biology, 2011; Stawicki et al., PLoSGenetics, 2013; Zhou et al., eLife, 2013). In our recent studies, we have discovered novel inter-tissue interactions in the regulation of neuronal circuits, and identified an immunoglobulin protein that plays instructive roles to control synapse numbers through phagocytosis (Cherra et al., Neuron, 2016).

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 (Chen et al., Neuron, 2011). Our current studies focus on the roles of the conserved MAPKKK DLK-1 and the microtubule regulator EFA-6 in axon regeneration (Yan et al., Cell 2009; Yan and Jin, Neuron, 2012; Chen et al., Neuron, 2011; Chen et al.,, eLife, 2015). By advancing our knowledge of intrinsic signaling pathways, we hope to develop new strategies to enhance regrowth ability of injured axons.

Novel applications of optogenetic methodology: Optogenetic manipulation of cells and molecules using genetically encoded tags is revolutionizing neurobiology. Mini Singlet Oxygen Generator (miniSOG) is a genetically encoded photosensitizer, created by R. Tsien's lab (Shu et al., PLoS Biology, 2011). We have employed the ability of inducible ROS generation by miniSOG to develop innovative optogenetic tools to perturb neural circuit (Qi et al., PNAS 2012) and to perform genome wide random mutagenesis (Noma and Jin, Nat. Comm. 2015).