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Dr. Chi-Kuang Yao
Assistant Research Fellow
Room 607, Institute of Biological Chemistry, Academia Sinica
128, Academia Road Sec. 2, Nankang, Taipei 115, Taiwan
TEL: +886-2-2785-5696 ext. 6070
FAX: +886-2-2788-9759

The goal of my lab is to understand the cellular and molecular mechanisms that underlie function, growth, and development of synapses in nerve system. The fruit fly is used as a model system to achieve our aims.

  The cell-cell specialized contacts, called synapses, are the fundamental units to support information exchange between neurons and their target cells, thereby linking most if not all neurons together to establish a complex network in nerve system. These communications mainly relies on synaptic transmission, a transition process of electric to chemical signal. The formation of this network and growth of synapses at particular connections are governed through coordinated signals between pre- and postsynaptic cells during development. Especially, neurons have unique feature, called plasticity, by which mature synapses enable to change their strengths in response to external stimuli by altering morphology or physiological properties. Finally, defects in synaptic transmission and growth are often associated with ageing and many human disorders, including mental retardation, epilepsy, and neurodegenerative disorders etc. Thus, exploring the detailed mechanisms underlying these processes will help us to gain insights into how neurons form synapses and communicate with postsynaptic cell and understand the molecular basis of synaptic plasticity and neurological diseases.

  Proper synaptic transmission is pivotal to many aspects of synaptic biology, including function, growth, and plasticity. This transmission is basically achieved by the repeated cycles of synaptic vesicle (SV) exocytosis and endocytosis (depicted in Figure 1). In exocytosis, SVs filled with neurotransmitters are recruited to and docked at release sites, called active zones. Upon the invasion of an action potential into the presynaptic terminals, membrane depolarizations spark voltage-gated Ca2+ channels (VGCCs), residing around active zones, to lead to a Ca2+ influx that triggers SV fusion. The release of transmitters following the fusion elicits postsynaptic responses. SVs are then recycled by SV endocytosis to sustain new rounds of exocytosis. Since repeated fusion of SVs leads to a gradual decline in the SV pool, the rate of SV endocytosis must be tightly coupled with the rate of SV exocytosis, thereby maintaining neuronal function. However, it remains poorly understood how this coupling is spatiotemporally regulated?

  Because of the complexity of the vertebrate brain and because genes often have redundant functions in vertebrates, it has been challenging to elucidate the in vivo function of specific proteins in synaptic biology. In addition, experiments with mammals are expensive and especially tedious when compared to fruit flies or worms. Finally, forward genetic screens in mice are very expensive. As a result, the fruit fly has been extensively used as a model system to isolate mutations in genes that have been proposed to play a role in synaptic transmission, to identify new genes that affect synaptic transmission, and to unravel the molecular basis of synaptic physiology. The genetic toolkit in flies is unrivaled and allows some of the most elegant and least intrusive in vivo manipulations. Importantly, a major tenant of this research is that the role of these proteins are evolutionarily conserved, which has been extensively documented already. Thus, by combining these tools with molecular, biochemical, imaging technology, and electrophysiology, my lab aims toward to unravel the role of specific proteins in the aforementioned processes. Two major aims in my lab are as follow.

Subject1: Mechanisms of Ca2+-regulated synaptic vesicle endocytosis and exo-endocytosis coupling
  From an unbiased forward genetic screen, we identified a novel synaptic vesicle-associated Ca2+ channel Flower as a key regulator of synaptic vesicle cycle. In our current model (depicted in Figure 1), intracellular Ca2+ at rest (20-80 nM) is increased to a range from 10 to 100 μM by a nerve stimulus which activates VGCCs. The high local Ca2+ spikes around active zones lead to SV fusion as well as accumulation of Flower into periactive zones. After these Ca2+ peaks drop, Flower in turn triggers another small Ca2+ influx (< 1 μM) to promote endocytosis. Later, endocytosis removes most, but not all, of the Flower protein, thereby performing a simple autoregulatory feed-back loop. Hence, this novel Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis. We are currently exploring what the ion conductance and selectivity of a single Flower channel are, how channel gating of Flower during SV cycle is regulated, what the structure of Flower is, and what the function of vertebrate Flower orthologs is.

Subject2: Mechanisms of synaptic growth
  Proper synaptic growth is fundamental to synaptic function, development, and plasticity. Intriguingly, fly larval neuromuscular junctions (NMJs) associated with loss of flower are vastly overgrown and exhibit a dramatic increase in the number of small satellite boutons (depicted in Figure 2). Currently, we are attempting to understand the cellular and molecular mechanisms underlying this aberrant synaptic growth.   In long-term run, my lab will try to fish out more new players involved in synaptic function and growth by doing new genetic screens or by using biochemical approaches.

2001,08 - 2005,06 Ph.D., Institute of Genetics, National Yang-Ming University, Taiwan R.O.C.
1999,08 - 2001,06 M.S., nstitute of Genetics, National Yang-Ming University, Taiwan R.O.C.
1995,09 - 1999, 06 B.S., Department of Biology, National Cheng Kung Univeristy, Taiwan R.O.C.

2011,10 - present Assistant research fellow, Institute of Biological Chemistry, Academia Sinica
2006,03 - 2011,08 Postdoctoral fellow, Department of Molecular and Human genetics, Baylor College of Medicine, TX, USA
2005,07 - 2006,02 Postdoctoral fellow, Institute of Molecular Biology, Academia Sinica

    Publications List
A Ca2+ channel differentially regulates Clathrin-mediated and activity-dependent bulk endocytosis.
Yao CK, Liu YT, Lee IC, Wang YT, Wu PY PLoS biology (2017)
Optomotor-blind negatively regulates Drosophila eye development by blocking Jak/STAT signaling.
Tsai YC, Grimm S, Chao JL, Wang SC, Hofmeyer K, Shen J, Eichinger F, Michalopoulou T, Yao CK, Chang CH, Lin SH, Sun YH, Pflugfelder GO PloS one (2015)
Mitochondrial fusion but not fission regulates larval growth and synaptic development through steroid hormone production.
Sandoval H, Yao CK, Chen K, Jaiswal M, Donti T, Lin YQ, Bayat V, Xiong B, Zhang K, David G, Charng WL, Yamamoto S, Duraine L, Graham BH, Bellen HJ eLife (2014)
A synaptic vesicle-associated Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis.
Yao CK, Lin YQ, Ly CV, Ohyama T, Haueter CM, Moiseenkova-Bell VY, Wensel TG, Bellen HJ Cell (2009)
Rab3 GTPase lands Bruchpilot.
Giagtzoglou N, Mahoney T, Yao CK, Bellen HJ Neuron (2009)
Differential requirements for the Pax6(5a) genes eyegone and twin of eyegone during eye development in Drosophila.
Yao JG, Weasner BM, Wang LH, Jang CC, Weasner B, Tang CY, Salzer CL, Chen CH, Hay B, Sun YH, Kumar JP Developmental biology (2008)
straightjacket is required for the synaptic stabilization of cacophony, a voltage-gated calcium channel alpha1 subunit.
Ly CV, Yao CK, Verstreken P, Ohyama T, Bellen HJ The Journal of cell biology (2008)
Upd/Jak/STAT signaling represses wg transcription to allow initiation of morphogenetic furrow in Drosophila eye development.
Tsai YC, Yao JG, Chen PH, Posakony JW, Barolo S, Kim J, Sun YH Developmental biology (2007)
Eyg and Ey Pax proteins act by distinct transcriptional mechanisms in Drosophila development.
Yao JG, Sun YH The EMBO journal (2005)

Updated 2017.03.08

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