Ph.D., 2002, HUST, China
Phone: (608) 263-6265 (O), (608)261-1540
(608) 265-7821 Fax
Vesicles are the smallest organelles in cells. Vesicle trafficking is a fundamental process for material and information exchanges in a cell's life. We study two types of vesicles: small synaptic vesicles in neurons and large dense-core vesicles in secretory cells. The goal is to gain deep, mechanistic understanding of the synaptic function and endocrine regulation in health and disease.
Our work lies at the interface of neuroscience, cell biology, and biophysics. We use state-of-the-art electrophysiology, live-cell imaging (e.g., TIRF and confocal imaging), molecular biology, and transgenic mouse model in our studies; our laboratory also develops cutting-edge new approaches, such as superresolution microscopy (e.g., PALM, d-STORM) and acute molecular activation/inactivation in living cells (e.g., optogenetic, photolysis).
1. Presynaptic function and development
Normal brain function relies on proper synaptic transmission and plasticity. Synaptopathy, disruption of synaptic structure and function, has been increasingly implicated in numerous brain disorders such as
Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, autism, and schizophrenia. We study the molecular and cellular mechanism of synaptic vesicle trafficking (release, regeneration, and transmitter reloading) and their role in synaptic development and plasticity. This work promises to gain a mechanistic understanding of synapses and to develop novel treatments for brain diseases. Using the calyx of Held synapse, a large presynaptic terminal in the auditory brainstem of rodents, we are currently focusing the mechanism of rapid exo-endocytosis coupling at active zones.
2. Dense core vesicle trafficking in beta cells
Large dense core vesicles control the release of hormones that are essential for diverse cell function and signaling. We use the pancreatic beta cell as a model cell to study dense core vesicle trafficking. Beta cells are the sole source of insulin production in mammals, and its dysfunction is the hallmark of diabetes. Our recent work discovers an endocytosis-dependent regulation of insulin secretion in beta cells. It highlights a potential link between beta cell endocytosis and diabetes, opening a new area of study.
3. Nano-machinery of vesicle release complex
Nearly all the key genes and molecules for vesicle trafficking have been identified. However, a clear picture of these components working together in native cells is still missing.
For example, prior vesicle fusion, the vesicle must dock at a release site containing SNARE, Ca2+ sensors, priming proteins, and Ca2+ channels.
We are interested in imaging the macromolecular architecture of release apparatus at the nanometer scale.
We are developing single-molecule localization superresolution microscopy (SMLM) and other innovative tools to understand the structure, dynamics, and regulation of the nano-machine in native cells
which is fundamental to transmitter release and hormone secretion.
- Mahapatra S, Fan F, Lou X. Tissue-specific dynamin-1 deletion at the calyx of Held decreases short-term depression through a mechanism distinct from vesicle resupply. Proc Natl Acad Sci U S A. 2016; 113(22):E3150-8. PMID: 27185948
- Fan F, Funk L, Lou X. Dynamin 1 and 3 mediated endocytosis is essential for the development of a large central synapse in vivo. J. Neurosci. 2016;36(22):6097-115. PMID: 27251629
- Mahapatra S, Lou X. Dynamin-1deletion enhances post-tetanic potentiation and quantal size after tetanic stimulation at the calyx of Held. J. Physiology (London) 2016. doi: 10.1113/JP271937
- Fan F, Ji C, Wu Y, Ferguson SM, Tamarina N, Philipson LH, Lou X. Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis. J. Clin. Invest. 2015; 125 (11): 4026-41. PMID: 26413867. Highlighted in the editor's Choice of J Clin Invest.
- Ji C, Zhang Y, Xu P, Xu T, Lou X. Nanoscale landscape of phosphoinositides revealed by the specific PH-domains using single-molecule superresolution imaging in the plasma membrane. J. Biol. Chem. 2015; 290 (45): 26978-93. PMID: 26396197
- Lou X*, Fan F, Messa M, Raimondi A, Wu Y, Looger LL, Ferguson SM, De Camilli P*. Reduced release probability prevents vesicle depletion and transmission failure at dynamin mutant synapses. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):E515-23. PMID:22308498 (*corresponding authors)
- Milosevic I, Giovedi S, Lou X, Raimondi A, Collesi C, Shen H, Paradise S, O'Toole E, Ferguson S, Cremona O, Camilli PD. Recruitment of endophilin to clathrin-coated pit necks is required for efficient vesicle uncoating after fission. Neuron. 2011 Nov 17;72(4):587-601. PMID: 22099461
- Raimondi A, Ferguson SM, Lou X, Armbruster M, Paradise S, Giovedi S, Messa M, Kono N, Takasaki J, Cappello V, O'Toole E, Ryan TA, De Camilli P. Overlapping role of dynamin isoforms in synaptic vesicle endocytosis. Neuron. 2011 Jun 23;70(6):1100-14. PMID: 21689597
- Kochubey O, Lou X, Schneggenburger R. Regulation of transmitter release by Ca2+ and synaptotagmin: insights from a large CNS synapse. Trends Neurosci. 2011 May; 34(5):237-46. Epub 2011 Mar 24. Review. PMID: 21439657
- Lou X, Paradise S, Ferguson SM, DeCamilli P. (2008) Selective saturation of endocytic capacity at a glutamatergic central synapse lacking dynamin 1. Proc. Natl. Acad. Sci. USA, 105(45):17555-60.
- Lou X, Korogod N, Brose N, Schneggenburger R. (2008) Phorbol esters modulate spontaneous and Ca2+-evoked transmitter release via acting on both Munc13 and protein kinase C.
J. Neurosci. 28(33):8257-67.
- Korogod N*, Lou X* (*equal contribution), Schneggenburger R. (2007) Posttetanic potentiation critically depends on an enhanced Ca2+ sensitivity of vesicle fusion mediated by presynaptic PKC. Proc. Natl. Acad. Sci. USA, 104(40):15923-8.
- Wolfel M, Lou X, Schneggenburger R. (2007) A mechanism intrinsic to the vesicle fusion machinery determines fast and slow transmitter release at a large CNS synapse. J. Neurosci. 27(12):3198-210.
- Lou X, Scheuss V, Schneggenburger R. (2005) Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature, 435(7041):497-501.
- Dulubova I, Lou X, Lu J, Huryeva I, Alam A, Schneggenburger R, Sudhof TC, Rizo J. A (2005) Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? EMBO J. 24(16):2839-50.
- Korogod N, Lou X, Schneggenburger R. (2005) Presynaptic Ca2+ requirements and developmental regulation of posttetanic potentiation at the calyx of Held. J. Neurosci. 25(21):5127-37.
- Wan QF, Dong Y, Yang H, Lou X, Ding J, Xu T. (2004) Protein kinase activation increases insulin secretion by sensitizing the secretory machinery to Ca2+. J. Gen. Physiology, 124(6):653-62.
- Lou X, Yu X, Chen XK, Duan KL, He LM, Qu AL, Xu T, Zhou Z. (2003) Na+ channel inactivation: a comparative study between pancreatic islet beta-cells and adrenal chromaffin cells in rat. J. Physiology (London), 548(1):191-202.
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