Positions

Professor
Baylor College of Medicine
Howard Hughes Medical Institute
Investigator
Faculty Senator
Baylor College of Medicine
March of Dimes Chair in Developmental Biology
Baylor College of Medicine

Education

MBA from University Of Brussels
DVM from University Of Ghent
PhD from University Of California, Davis
Post-Doctoral Fellowship at University Of Basel

Professional Interests

  • Mitochondria and neuronal degeneration, and technology development

Professional Statement

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 165 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. More importantly, the information we derive from our characterization of these fly mutants can be synergized with ongoing work in clinics, as the human homologs of the fly genes have been found to be associated with diseases.

Technology Development: My lab (as part of the Drosophila Gene Disruption Project) develops new tools and reagents, which we make freely available to the Drosophila community. My lab has 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 ~65 percent of all fly genes are available from the Bloomington Drosophila Stock Center and the Gene Disruption Project (GDP) Database (http://flypush.imgen.bcm.tmc.edu/pscreen/). We have expanded the size and utility of this collection by creating strains carrying the 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. Using this strategy we have generated a library of GFP-tagged genes that we have shared publically. We demonstrated that with this technique, genes can be knocked down reversibly, spatially, and temporally by RNAi against GFP (iGFPi) as well as by deGradFP technology. Hence, this strategy and collection of strains allows sophisticated in vivo manipulations for many genes. In addition, we have also created a new transgenesis platform for flies. The P[acman] (phiC31 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.

Selected Publications