Faculty

Curriculum Vitae | Research Interests | Selected publications

Curriculum Vitae

• B.S., Biochemistry, Wuhan University, P. R. China 1989-1993
• M.S., Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, P. R. China 1993-1996
• Ph.D. Neurobiology, University of Alabama at Birmingham, 1996-2001
• Postdoc, Molecular and Human Genetics, Baylor College of Medicine, 2001-2006
• Assistant Professor, Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, January 2007-present

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Research Interests

The research in my laboratory is directed toward understanding the genetic and cellular basis of neural development, maintenance and degeneration using the fruit fly Drosophila melanogaster as a model system.

The Drosophila model system

The central and peripheral nervous systems of Drosophila are remarkably similar to vertebrates functionally and morphologically.  The specific advantages of the Drosophila model system for neurobiology include the following: First, Drosophila is an organism simple enough to allow large scale genetic screens to identify novel components in neuronal processes. Especially the recent development of genetic tools such as the FLP/FRT system allows the generation of mosaic flies where only a subset of neurons are rendered homozygous for the mutation, while the rest of tissues are heterozygous. These genetic tools make it possible to study the neuronal phenotypes of lethal mutations in the adult nervous system. Second, the nervous system of Drosophila is complex enough to resemble that of vertebrates in basic functions and morphology. Some fundamental mechanisms and key components of processes such as neurodevelopment, neural fate specification, and synaptic transmission are conserved between flies and vertebrates. Therefore, we could take advantage of the genetic capacity of the Drosophila model system to dissect complex neuronal mechanisms which will help us understand the functions of the vertebrate nervous system.

Project 1 Molecular Mechanisms of neurodegeneration 

From the forward genetic screen designed to isolate mutations that cause neuronal malfunction in the adult brain, we have identified mutations in a gene called nmnat that cause a rapid and severe neurodegeneration immediately after the completion of neuronal differentiation and development.  Interestingly, preliminary studies show that overexpression of NMNAT in the nervous system has potent neuroprotective effects in activity induced neurodegeneration. These findings suggest that NMNAT protein is required to maintain neuronal integrity and this function can be exploited to protect neurons from degeneration under adverse conditions. Our discovery of such a neuronal ‘maintenance factor’ reveals that neurons constantly protect themselves against toxic insults and a failure of this defense system for example due to a genetic mutation leads to neurodegeneration or neuronal death.  Understanding the details of the defense mechanism will not only provide insights into the cellular process of neuronal maintenance, but also offers a unique angle to tackle the mechanisms of neurodegeneration.

The preliminary studies on NMNAT have uncovered a novel pathway that neurons use to maintain integrity and defend against neurodegeneration.  Currently, our research is focused on characterizing the biochemical and cellular mechanisms underlying the protective process, identifying the molecular players and the regulatory components of this process, and analyzing the protective effects that NMNAT offers in various neurodegenerative disease models.  The knowledge obtained from this research and the mutant fly strains generated throughout the study will be immediately applied to the therapeutic design and drug screening for the treatment of neurodegenerative disorders, and guide us in future studies in mice, and hopefully humans.

Project 2 Mechanisms of synapse development

The establishment of synapses is required for neuronal function. However, the molecular components of active zone structures in both mammalian and Drosophila synapses are largely unknown and how active zones are assembled and maintained are unclear.  From the screen, I have isolated mutants with specific defects in synapse formation.  A defect in synapse formation can be caused by (1) missing a structural component of the synaptic active zone, (2) malfunction of the regulation of synapse assembly, or (3) disruption of synapse maintenance. Interestingly, from our screen, I have isolated three mutations that would likely fall into each of the above three categories.  The first mutation, named barless (barls), has a very specific active zone structural phenotype in which the ‘platform’ of the dense projection is missing and the ‘pedestal’ is elongated compared to wild type. It is very likely that the building blocks of the platform are missing in these mutants, which would be an example of category (1).  The second mutation, named synmay, is the only group among 60 mutant alleles screened that has fewer synapses in the photoreceptor terminals. We have shown that the precision of synapse numbers is controlled cell-autonomously by the presynaptic photoreceptor (Hiesinger et al., 2006).  Identifying and characterizing synmay will unveil this cell-autonomous genetic program (category (2)).  The third mutation, named nmnat, has amorphous active zones that disintegrate rapidly with age.  I have already identify the gene and demonstrated that NMNAT is required to maintain the neuronal and synaptic integrity and functions as a ‘rejuvenating’ factor in mature neurons to protect them from ‘wear and tear’, i.e. usage-dependent degeneration (Zhai et al., 2006). 

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Recent Publications

Zhai, RG*, Zhang F, Hiesinger PR, Cao Y, Haueter CM, and Bellen HJ (2008) NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature 452(7189):887-91*corresponding author.  Featured Highlight in Nature Reviews Neuroscience 9, 323. Wiedemann, C.  Neurodegenerative disease: Understanding and preventing total catastrophe

Zhai, RG (2008) The architecture of the presynaptic release site. In Molecular Mechanisms of Neurotransmitter Release, ed. Wang ZW. The Humana Press Inc.

Zhai, RG, Cao Y, Hiesinger PR, Zhou Y, Mehta SQ, Schulze KL, Verstreken P, and Bellen HJ (2006) Drosophila NMNAT maintains neural integrity independent of its NAD synthesis activity. PLoS Biology 4(12): e416.

Hiesinger, PR*, Zhai, RG*, Zhou Y, Koh T-W, Mehta SQ, Verstreken P, Schulze KL, CaoY, Clandinin TR, Fischbach K-F, Meinertzhagen IA, and Bellen HJ (2006) Activity-independent pre-specification of synaptic partners in the visual map of Drosophila. Current Biology 16: 1835-1843. *co-first authors

Hiesinger, PR, Fayyazuddin A, Mehta SQ, Rosenmund T, Schulze KL, Zhai RG, Verstreken P, Cao Y, Zhou Y, Kunz J, and Bellen H J. (2005) The v-ATPase V0 subunit a1 is required for a late step in synaptic vesicle exocytosis in Drosophila. Cell 121(4):607-620.

\Mehta SQ, Hiesinger PR, Beronja S, Zhai RG, Schulze KL, Verstreken P, Cao Y, Zhou Y, Tepass U, Crair MC, and Bellen HJ. (2005) Mutations in Drosophila sec15 reveal a function in neuronal targeting for a subset of exocyst components. Neuron 46(2): 219-32.

Zhai, RG, Bellen HJ. (2004) Hauling t-SNAREs on Microtubule Highway Nature Cell Biology 6:918-919.

Zhai, RG, Bellen HJ. (2004) The Architecture of the Active Zone in the Presynaptic Nerve Terminal. Physiology  19: 262-270.

Verstreken P, Koh TW, Schulze KL, Zhai RG, Hiesinger PR, Zhou Y, Mehta SQ, Cao Y, Roos J, Bellen HJ. (2003) Synaptojanin Is Recruited by Endophilin to Promote Synaptic Vesicle Uncoating. Neuron 40(4):733-748.

Zhai, RG, Hiesinger PR, Verstreken P, Koh T-W, Schulze  K, Greenbaum M, Cao Y, Bellen BJ. (2003) Mapping of Drosophila mutations with molecularly mapped P-elements. Proc. Natl. Acad. Sci. U.S.A. 100(19):10860-5. Featured Highlight in Nature Reviews Genetics 4, 849. Casci, T. I can name it in three…

Shapira, M*, Zhai RG* , Dresbach T, Bresler T, Torres VI, Gundelfinger ED, Ziv NE and Garner CC. (2003) Unitary Assembly of Presynaptic Active Zones from Piccolo-Bassoon Transport Vesicles. Neuron 38(2): 237-252.  * Co-first authors

Garner, CC, Zhai RG, Gundelfinger ED, Ziv NE. (2002) Molecular mechanisms of CNS synaptogenesis. Trends in Neuroscience 25(5): 243-51.

Zhai, RG, Vardinon-Friedman H, Cases-Langhoff C, Becker B, Gundelfinger ED, Ziv NE and Garner CC. (2001) Assembling the Presynaptic Active Zone, the Identification of an Active Zone Precursor Vesicle. Neuron 29(1): 131-143.

Bresler T, Ramati Y, Zamorano PL, Zhai R, Garner CC, Ziv NE. (2001) The dynamics of sap90/psd-95 recruitment to new synaptic junctions. Mol Cell Neurosci;18(2):149-167.

Fenster, SD*, Chung WJ*, Zhai R* Cases-Langhoff C, Voss B, Garner AM, Kampf U, Gundelfinger ED, and. Garner CC. (2000) Piccolo, a presynaptic zinc finger protein structurally related to Bassoon. Neuron 25(1): 203-214.        * Co-first authors

Zhai, R, Olias G, Chung WJ, Lester RAJ, tom Dieck S, Langnaese K, Kreutz MR, Kindler S, Gundelfinger ED and Garner CC. (2000) Temporal appearance of the presynaptic cytomatrix protein Bassoon during synaptogenesis. Molecular Cellular Neuroscience, 15(5):417-28.

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