Research Interests:
Our research group is interested in the organization and dynamics of biological circuits underlying neuronal development and synapse function in health and disease. We use mouse models, cutting-edge live-cell imaging approaches and chemical genetics to tackle this problem at the level of individual neurons and synapses, in culture or in vivo. Current projects in the lab focus on (i) feedback circuits in neuronal polarization and axon regeneration, (ii) axonal transport defects in models for Schizophrenia and Parkinson disease, (iii) Store-Operated Ca2+ entry in synaptic transmission and plasticity and (iv) miRNAs in presynaptic differentiation and axon regeneration.
1. Growth-promoting circuits in neuronal polarization, axon growth and regeneration
(collaboration with Takanari Inoue, Johns Hopkins)
During development of the nervous system, neurons show a remarkable capacity for growth, often projecting their axons over considerable distances to form proper synaptic connections. Neurons of the central nervous system (CNS) progressively lose, however, this intrinsic capacity for growth as they age. This decline in growth potential is now thought to be an important factor underlying the poor regenerative response of adult CNS neurons. Our research on this topic aims to identify the intracellular signaling circuits underlying “spontaneous” axonal growth early in development. Our long-term goal is to re-activate these growth-promoting circuits in adult CNS neurons to promote neuroregeneration. Our efforts are currently centered on identifying local and rapid feedback circuits that regulate axon elongation early in development or immediately after injury. We have also recently begun to investigate the role of miRNAs in regulating local protein synthesis in the axonal growth cone and regeneration.
2. Axonal transport defects in neurodevelopmental and neurodegenerative diseases
(collaboration with Zeng Li, NNI and Kah Leong Lim, NUS)
Most major neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease or amyotrophic lateral sclerosis (ALS) display axonal transport defects. Disruption of axonal transport is an early and perhaps causative event in many of these diseases, suggesting that this process is of potential therapeutic relevance. With the advent of induced pluripotent stem cells (iPSCs) and automated live-cell microscopy, it is now conceivable to systematically analyze axonal transport defects in iPSC-derived neurons from individuals affected by neurodegenerative diseases or other neurological disorders. The development of such an assay would represent a powerful new tool for early disease diagnostics and drug screening. Our lab has developed an imaging platform for high-content analysis of axonal transport events. This platform is based on a microfluidic chamber which aligns axon growth along parallel micro-channels, thereby greatly facilitating the acquisition and analysis of time-lapse transport data. Using this approach, we are currently studying axonal transport defects in mouse and cellular models of Parkinson disease and Schizophrenia.
3. Store-Operated Calcium Entry (SOCE) in synaptic plasticity
(Collaboration with George Augustine, DUKE-NUS)
Store-operated Ca2+entry (SOCE), also referred to as capacitative Ca2+ entry (CCE), is the predominant Ca2+ influx pathway in non-excitable cells, but its function in the nervous system is controversial. This Ca2+ entry pathway is turned on in response to Ca2+ depletion from the endoplasmic reticulum (ER) and is regulated by the ER-localized Ca2+ sensors STIM1 and STIM2. Using a combination of optical and electrophysiological measurements in cultured neurons and brain slices, we are probing the role STIM and SOCE in neurotransmission and synaptic plasticity.
4. miRNAs in presynaptic differentiation
(collaboration with Mathijs Voorhoeve, DUKE-NUS)
Micro-RNAs (miRNAs) are short, non-conding RNA molecules, which bind to complementary sequences in the 3’UTR of target mRNAs, usually resulting in gene silencing. The human genome encodes over 1000 miRNAs which target an estimated 60% of all genes. miRNAs are highly expressed in the brain and have been implicated in neurogenesis, neuronal fate, dendritic spine morphogenesis and neurological disorders. Less is known about the role of miRNAs in axonal and presynaptic development. Our goal is to identify novel miRNAs that specifically regulate the differentiation of an axonal terminal into a functional presynaptic zone.
Selected Publications:
Hierarchical temporal processing deficit model of reality distortion and psychosis. Krishnan RR, Fivaz M, Krauz, MS and Keefe, R. Molecular Psychiatry 2011 Feb;16(2):129-44
Wong L. C, Lu B, Tan K. W, and Fivaz M., Fully-automated image processing software to analyze calcium traces in populations of single cells. Cell Calcium 2010 (48) 270-274
Ng CH, Mok SZ, Koh C, Ouyang X, Fivaz M, EK Tan, Dawson VL, Dawson TM, Yu F, Lim KL. Parkin
protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila. J. Neurosci. 2009 Sept 9;29(36):11257-62
Li Y and Fivaz M. Feedback-mediated neuronal competition for survival cues regulates innervation of a target tissue. BioEssays 2008 Oct;30(10):929-33
Fivaz M, Bandara S, Meyer T. Robust neuronal symmetry-breaking by HRas-triggered local positive feedback. Curr Biol. 2008 Jan 8;18(1):44-50
Liou J, Fivaz M, Inoue T, Meyer T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. PNAS 2007 May 21.
Fivaz, M, and Meyer T. Reversible intracellular translocation of KRas but not HRas in hippocampal neurons regulated by Ca2+/CaM. J Cell Biol 2005 170(3) : 429-41.
Fivaz M, Vilbois F, Thurnheer S, Pasquali C, Abrami L, Bickel PE, Parton RG, Van Der Goot FG. Differential sorting and fate of endocytosed GPI-anchored proteins. EMBO J. 2002; 21(15):3989-4000.
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