Hugo J. Bellen, D.V.M., Ph.D.
Professor of Molecular and Human Genetics
M.B.A., University of Brussels, 1976
D.V.M., University of Ghent, 1983
Ph.D., Genetics, University of California, Davis, 1986
Postdoc, Cell Biology, Biozentrum, University of Basel, 1989
Mitochondria and Neuronal Degeneration
To understand the molecular mechanisms underlying neurodegeneration, we performed an unbiased forward genetic screen to isolate mutants that display progressively deteriorating neuronal function. We first created a collection of 6,000 mutations on the Drosophila X-chromosome that each cause lethality when homozygous. We then induced homozygous mutant clones in the compound eye in otherwise viable heterozygous animals and recorded electroretinograms (ERGs -- a measure of eye activity upon exposure to light) at days 1-3 and at days 24-30. Mutants whose ERGs progressively worsened with time were kept. This primary screening strategy was followed by a secondary screening strategy using morphology as a readout. Using Transmission Electron Microscopy (TEM) of the photoreceptor neurons, we documented the progressive demise of the neurons. We then mapped and assigned the mutations to complementation groups and estimate that we have isolated about 120 genes that cause a neurodegenerative phenotype when mutated. We are currently characterizing a few of these loci and are mapping many more. We hope to gain a much better understanding of the molecular mechanisms by which neurodegeneration occurs.
Our goal is to define the role of specific proteins in exo- and endocytosis of synaptic vesicles. These include proteins previously implicated on the basis of biochemical experiments as well as new proteins isolated through genetic screens in my lab. Through forward and reverse genetic screens, we have identified mutations in numerous genes that affect neurotransmitter release and have defined their function in vivo. By combining genetic analyses, protein localization studies, electrophysiological recordings, FM 1-43 dye uptake experiments and TEM at the neuromuscular junction (NMJ), we have provided valuable insights into the function of essential synaptic proteins, including synaptotagmin, syntaxin, tweek, flower, dap160, endophilin, synptojanin, etc.
My lab (together with Drs. Hoskins and Spradling) develops new tools and reagents, which we make freely available to the Drosophila community. My lab has generated more than 12,000 publicly available stocks carrying single transposable element insertions that can be imprecisely excised to create mutations. This is the most commonly used method to create mutations in fly genes using reverse genetics. Currently, insertions in ~65 percent of all fly genes are available from the Bloomington Drosophila Stock Center and the Gene Disruption Project (GDP) Database. We are now expanding the size and utility of this collection by creating strains carrying a new transposable element, MiMIC (Minos Mediated Integration Cassette). MiMIC inserts preferentially in introns and allows integration of any DNA in a gene of interest based on Recombination Mediated Cassette Exchange, enhancing our ability to genetically manipulate flies. In addition, we have also created a new transgenesis platform for flies. The P[acman] (ΦC31 artificial chromosome for manipulation) vector allows integration of large DNA fragments. Based on this technology, we constructed two highly versatile, publicly available whole-genomic libraries that allow manipulation of virtually all fly genes (http://www.pacmanfly.org/). They provide direct access to recombineering- and transformation-ready genomic clones that can be integrated at precise locations in the Drosophila genome. Tagged clones allow one to assess gene expression and protein distribution and to efficiently rescue mutations and deletions.
- Xiong B, Bayat V, Jaiswal M, Zhang K, Sandoval H, Charng WL, Li T, David G, Duraine L, Lin YQ, Neely GG, Yamamoto S, Bellen HJ (2012). Crag is a GEF for Rab11 required for rhodopsin trafficking and maintenance of adult photoreceptor cells. PLoS Biol. 10(12): e1001438. PubMed PMID: 23226104
- Yamamoto S, Charng WL, Rana NA, Kakuda S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Wang H, Haltiwanger RS, Bellen HJ (2012). A mutation in EGF repeat 8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science 338(6111): 1229-32. PubMed PMID: 23197537
- Venken KJT, Schulze KL, Haelterman N, Pan H, He Y, Evans-Holm M, Carlson JW, Levis RW, Spradling AC, Hoskins RA, Bellen HJ (2011). MiMIC: a highly versatile transposon insertion resource for engineering Drosophila melanogaster genes. Nat. Methods 8(9): 737-43. PubMed PMID: 21985007
- Yao CK, Lin YQ, Ly CV, Ohyama T, Haueter CM, Moiseenkova-Bell VY, Wensel TG, Bellen HJ (2009). A synaptic vesicle-associated Ca2+ channel promotes endocytosis and couples exocytosis to endocytosis. Cell 138(5): 947-60. PubMed PMID: 19737521
- 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 133(6): 963-77. PubMed PMID: 18555774
- 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(7189): 887-91. PubMed PMID: 18344983
- Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ (2008). Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell 132(2): 247-58. PubMed PMID: 18243100
- 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(5806): 1747-51. PubMed PMID: 17138868
- 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(4): 607-20. PubMed PMID: 15907473
- 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(1): 101-12. PubMed PMID: 11955450
- Lloyd T, Atkinson R, Wu MN, Pennetta G, Bellen HJ (2002). HRS regulates endosome membrane invagination and tyrosine kinase receptor signaling in Drosophila. Cell 108(2): 261-9. PubMed PMID: 11832215
Hugo J. Bellen, D.V.M., Ph.D.
Howard Hughes Medical Institute
Baylor College of Medicine
One Baylor Plaza, MS BCM235
Houston, TX, 77030, U.S.A.
Web site: Bellen Lab