Hugo Bellen, Ph.D.
Professor, Molecular & Human Genetics, Molecular & Cellular Biology, and Neuroscience
Baylor College of Medicine
M.B.A., University of Brussels, Belgium, 1976
D.V.M., University of Ghent, Belgium, 1983
Ph.D., University of California at Davis, 1986
Postdoc, University of Basel, Biozentrum, Switzerland, 1989
Mitochondria and Neuronal Degeneration
To study the mechanisms by which mutations in specific genes cause neurodegeneration we performed a forward genetic screen to isolate mutations in neurodegenerative genes in an unbiased fashion. To perform this screen we first created 6,000 homozygous lethal mutations on the Drosophila X-chromosome. We then induced homozygous mutant clones in the compound eye 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 of the photoreceptor neurons, we documented the progressive demise of the neurons. We then mapped and assigned the mutations to complementation groups. We estimate that we have isolated about 120 genes that cause a neurodegenerative phenotype when mutated. We are currently characterizing about 10 of these loci and are mapping many more. We estimate that we will have point mutations in about 65 loci whose human homologue cause neurodegenerative disease. We hope to use this collection of mutants 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.
The lab (together with Drs. Hoskins and Spradling) develops new tools and reagents, that we make freely available to the Drosophila community. We have generated more than 15,000 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 approximately 70 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 usefulness 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 manipulate flies. 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 (see P[acman] Resources).
Zhang K, Li Z, Jaiswal M, Bayat V, Xiong B, Sandoval H, Charng WL, David G, Haueter C, Yamamoto S, Graham BH and Bellen HJ. The C8ORF38 homologue Sicily is a cytosolic chaperone for a mitochondrial complex I subunit. J Cell Biol, 200(6):807-20 (2013). PubMed
Xiong B, Bayat V, Jaiswal M, Zhang K, Sandoval H, Charng WL, Li T, David G, Duraine L, Lin YQ, Neely GG, Yamamoto S and Bellen HJ. Crag is a GEF for Rab11 required for rhodopsin trafficking and maintenance of adult photoreceptor cells. PLoS Biol, 10(12):e1001438 (2012). PubMed
Yamamoto S, Charng WL, Rana NA, Kakuda S, Jaiswal M, Bayat V, Xiong B, Zhang K, Sandoval H, David G, Wang H, Haltiwnager RS and Bellen HJ. A mutation in EGF repeat-8 of Notch discriminates between Serrate/Jagged and Delta family ligands. Science, 338(6111):1229-32 (2012). PubMed
Jaiswal M, Sandoval H, Zhang K, Bayat V and Bellen HJ. Probing mechanisms that underlie human neurodegenative diseases in Drosophilia. Annu Rev Genet, 46:371-96 (2012). PubMed
Bayat V, Thiffault I, Jaiswal M, Tétreault M, Donti T, Sasarman F, Bernard G, Demers-Lamarche J, Dicaire MJ, Mathieu J, Vanasse M, Bouchard JP, Rioux MF, Lourenco CM, Li Z, Haueter C, Shoubridge EA, Graham BH, Brais B and Bellen HJ. Mutations in the mitochondrial methionyl-tRNA syntetase cause a neurodegenerative phenotype in flies and a recessive ataxia (ARSAL) in humans. PLoS Biol, 10(3):e1001288 (2012). PubMed
Giagtzoglou N, Yamamoto S, ZItserman D, Graves HK, Schulze KL, Wang H, Klein H, Roegiers F and Bellen HJ. dEHBP1 controls exocytosis and recycling of Delta during asymmetric divisions. J Cell Biol, 196(1):65-83 (2012). PubMed
Venken KJ, Simpson JH and Bellen HJ. Genetic manipulation of genes and cells in the nervous system of the fruit fly. Neuron, 72(2):202-30 (2011). PubMed
For more publications, see listing on PubMed.
Department: Molecular and Human Genetics
Address: Room T628
Baylor College of Medicine
One Baylor Plaza
Houston, TX 77030