Yishi Jin, PhD
Distinguished Professor and Chair
Department of Cellular and Molecular Medicine
University of California, San Diego School of Medicine
November 13, 2018
Molecular Genetic Mechanisms Regulating Synapses and Axon Regeneration
The synapse is the area where two neurons meet, where messages are sent, where connections are strengthened or weakened. An understanding of the complexities of the synapse is a major question in neuroscience research. Dr. Jin uses the worm C. elegans as a model organism for studying the intricacies of the synapse. Her work has examined remodeling of synapses during stages of larval development. Her lab has determined that a specific receptor helps control the excitation of locomotor neurons, which need a balance of excitation and inhibition in order to control worm movement. Dr. Jin also discussed her research into the genetic basis for axon regeneration after injury. Her lab has uncovered regulators important for axon regeneration, which could have implications for human neuronal repair following injury.
Synapses are compact subcellular structures that transmit information in the nervous system. A presynaptic terminal contains neurotransmitter-filled synaptic vesicles clustered around the active zone at the plasma membrane, and a postsynaptic receptive zone which is densely packed with neurotransmitter receptors, scaffold proteins and signal transduction machinery. Understanding of how synaptic components come together to be localized correctly has been a central question in neuroscience. Additionally, neural circuits are often modified to meet dynamic needs throughout a lifetime. My lab has taken integrated approaches, starting from forward genetic screens, to dissect the intricate molecular interactions in synapse formation and neuronal plasticity during development and in response to traumatic injury.
C. elegans has been a prime model organism for gene-discovery and for understanding the mechanisms of synapse and circuit plasticity with unique resolution. We focus on the locomotor circuit because a distinct class of neurons undergoes a dramatic synaptic remodeling in larval development and because the operation of this circuit requires coordination of balanced excitation and inhibition. Over four decades ago, pioneering studies by John G. White uncovered a dramatic connectivity switch involving a complete dendro- axo reversal of an inhibitory class of motor neurons, named ‘DD synapse remodeling’. Using in vivo synapse reporter, we first determined that DD synapse remodeling occurs within a defined time period beginning at late first larval stage and completing by early third larval stage. Through forward genetic analyses, we revealed that the timing of DD synapse remodeling is under negative inhibition by the nuclear factor LIN-14 and positive regulation by the MYRF proteins. We further dissected the cellular process of synapse elimination and reformation, and defined a mechanism involving dynamic microtubules, which coordinates directional trafficking of motor proteins with their synapse cargos.In adult C. elegans the locomotion circuit controls body muscle contraction via balanced cholinergic excitation and GABAergic inhibition to generate sinusoidal movement. Through genetic screening, we identified a neuronal nACh receptor that acts in the cholinergic motor neurons to control their excitability. Moreover, we characterized a gain-of- function (gf) mutation in a key subunit of this channel that causes excess cholinergic excitation and reduced GABAergic inhibition. Both the molecular lesion and the physiological basis of this mutant share striking similarities with mutations found in human epilepsy. Excitation/Inhibition (E/I) imbalance is widely implicated in neurological and psychiatric diseases. We have exploited C. elegans genetics to uncover genes and pathways that modulate E/I imbalance.
The ability of neurons to respond to injury is vital for protecting circuit’s function. We have established an in vivo axon injury model to discover conserved genes functioning in axon regeneration. Using this single axon injury assay in C. elegans, we systematically screened the function of >1200 selected C. elegans genes, based on the orthology to human genes and potential neuronal function or known biochemical role (Chen et al., Neuron 2011; Kim et al., 2018). Among numerous axon regeneration pathways identified, we have elucidated signaling pathways for DLK-1 MAP kinases, and characterized cellular dynamics in response to axon injury. Moreover, besides their pivotal roles in axon regeneration, emerging evidence has also begun to uncover the roles of the DLK family of kinases in injury- triggered neuronal survival and axon degeneration. Similarly, studies of other C. elegans axon regeneration regulators have expanded our knowledge in neuronal cytoskeleton and RNA-mediated regulation. It is our firm belief that neuronal response to traumatic injury is fundamentally conserved in evolution and that deep understanding of genes and pathways discovered in C. elegans will continue to expand our knowledge relevant to the health of humans.