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Genetic and molecular analysis of neurotransmitter release and nervous system development in Drosophila
Communication within the nervous system involves neurotransmitter release from synaptic vesicles that fuse with
the presynaptic membrane following a calcium influx during an action potential. The biochemical and molecular events underlying
neurotransmitter release and the trafficking of synaptic vesicles within the presynaptic terminal are currently being intensely
investigated. We and others have shown that proteins implicated in neurotransmitter release in vertebrates have been extremely
well conserved during evolution. Hence, it has been relatively straightforward to isolate the Drosophila homologues of
vertebrate proteins implicated in synaptic vesicle trafficking and to create mutations in the corresponding genes using a
reverse genetic approach. The fruitfly, Drosophila, is an excellent model system to study this question because the awesome
power of genetics combined with the availability of several functional assays, including sophisticated electrophysiological and
electron microscopy paradigms, allow us to describe the defects associated with these mutations. These studies combined
with FM1-43 dye-uptake experiments allow us to determine when and where these proteins are precisely required in the synaptic
vesicle cycle. Our laboratory presently focuses on Hrs, Endophilin, Synaptojanin, DAP160 and sample of novel proteins identified in
forward genetic screens.
To gain a more fundamental insight into the molecular mechanisms of the development of the nervous system and the
process underlying neurotransmitter release, we have performed chemical and P element mutagenesis screens to identify
mutations that affect the development of the peripheral nervous system. More than 30 novel genes have presently been isolated. We are
presently focusing on the gene senseless. The senseless gene is required for proper development of most cell types of the embryonic and adult
peripheral nervous system (PNS) of Drosophila. Senseless is a nuclear protein with four Zn-fingers that is expressed and
required in the sensory organ precursors (SOP) for proper proneural gene expression. Ectopic expression of Senseless in many
ectodermal cells causes induction of PNS external sensory organ formation and is able to recreate an ectopic proneural field. Hence,
senseless is both necessary and sufficient for PNS development. Our data indicate that proneural genes activate senseless
expression. Senseless is then in turn required to further activate and maintain proneural gene expression. This feedback mechanism
is essential for selective enhancement and maintenance of proneural gene expression in the SOPs.
Selected Publications
Lloyd TE, Atkinson R, Wu MN, Zhou Y, Pennetta G, Bellen HJ (2002) Hrs regulates endosome membrane
invagination and tyrosine kinase receptor signaling in Drosophila. Cell 108:261-269.
Verstreken P, Kjaerulff O, Lloyd TE, Atkinson R, Zhou Y, Meinertzhagen IA, Bellen HJ (2002) Endophilin
mutations block clathrin-mediated endocytosis but not neurotransmitter release. Cell 109:101-112.
Jafar-Nejad H, Acar M, Nolo R, Lacin H, Pan H, Parkhurst SM, Bellen HJ (2003) Senseless acts as a binary
switch during sensory organ precursor selection. Genes and Development 17:2966-2978.
Bellen HJ, Levis R, Rhem EJ, Liao G, He Y, Carlson JW, Tang G, Hiesinger PR, Schulze KL, Rubin GR, Hoskins
RA, Spradling AC (2004) The BDGP gene disruption project: single transposon insertions associated with 40% of Drosophila
genes. Genetics 167:761-781.
Mehta SQ, Hiesinger PR, Beronja S, Zhai RG, Schulze KL, Verstreken P, Cao Y, Zhou Y, Tepass U, Crair MC, Bellen HJ
(2005) Mutations in Drosophila sec15 reveal a function in neuronal targeting for a subset of exocyst components.
Neuron 46:219-232.
Hiesinger PR, Fayyazuddin A, Mehta SQ, Rosenmund T, Schulze KL, Zhai RG, Verstreken P, Cao Y, Zhou Y, Kunz J,
Bellen HJ (2005) The v-ATPase V0 subunit a1 is required for a late step in synaptic vesicle exocytosis
in Drosophila. Cell 121:607-620.
Venken KJT, He Y, Hoskins RA, Bellen HJ (2006) P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science
314:1747-1751.
Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ (2008) Rumi, a CAP10 domain protein, is a glycosyltransferase that modifies
Notch and is required for Notch signaling. Cell 132:247-258.
Zhai RG, Zhang F, Hiesinger PR, Cao Y, Haueter CM, Bellen HJ (2008) NAD synthase NMNAT acts as a chaperone to protect against neurodegeneration. Nature
452:887-991.
Tsuda H, Han SM, Yang Y, Tong C, Lin YQ, Mohan K, Haueter C, Zoghbi A, Harati Y, Kwan J, Miller MA, Bellen HJ (2008) The Amyotrophic Lateral Sclerosis 8 protein VAPB is
cleaved, secreted, and acts as a ligand for Eph receptors. Cell, in press.
Contact Information
- Hugo J. Bellen, D.V.M., Ph.D.
- Howard Hughes Medical Institute
- Baylor College of Medicine
- One Baylor Plaza T628
- Houston, Texas 77030, U.S.A.
- Lab website
- Tel: (713) 798-5272
- Fax: (713) 798-3694
- E-mail: hbellen@bcm.edu
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