Hugo Bellen, D.V.M., Ph.D.
Chair in Neurogenetics at the Jan and Dan Duncan Neurological Research Institute
Charles Darwin Professor in Molecular and Human Genetics
March of Dimes Professor in Developmental Biology, Professor of Neuroscience
Director, Graduate Program in Developmental Biology, Baylor College of Medicine
Investigator, Howard Hughes Medical Institute
The Bellen lab's interest in neurodegeneration recently led them to carry out the first comprehensive screen for essential genes that cause neurodegeneration in flies. Out of 35,000 stocks mutagenized with low EMS concentrations, they identified ~120 mutants with a neurodegenerative defect and the corresponding gene for more than 20 complementation groups. About 30% of the genes encode proteins that are implicated in human neurodegenerative disorders; the remaining 70% encode proteins that have not been previously characterized. The lab is trying to define the precise function of many of these proteins to better understand how they cause neuronal dysfunction. Through the use of large-scale genetic mosaic screens, the Bellen lab has also identified numerous genes involved in peripheral nervous system development, including a number that affect Notch signaling. One of the new genes is rumi, which encodes a sugar-modifying enzyme that alters the sugar composition of Notch EGF (epidermal growth factor) repeats and affects all the known functions of Notch. The lab also discovered that a series of proteins that control actin polymerization affect the formation of an actin structure in sensory organ precursor cells (SOPs) and impair Notch signaling during the specification of the SOPIIb.
In another major line of research, the Bellen lab has isolated seven key players in endocytosis: AP180, synaptojanin (synj), endophilin (endo), dynamin-associated protein/intersectin (Dap160), eps15, tweek, and flower. These genes encode proteins that are dramatically enriched in the nervous system and localized to nerve terminals, including the neuromuscular junctions (NMJs). There appear to be three major forms of endocytosis at fly NMJs: a fast kiss-and-run mode of release at active zones, a slower clathrin-mediated form in periactive zones, and bulk endocytosis of membrane. The presence of at least two modes of retrieval has been documented in hippocampal neurons but may not occur in all synapses.
Finally, the lab is attempting to create a transposable element insertion in every Drosophila gene. In collaboration with the laboratories of Allan Spradling (HHMI, Carnegie Institution of Washington) and Roger Hoskins (Lawrence Berkeley National Laboratory), the Bellen group has created insertions in more than 60 percent of all Drosophila genes. They have also developed a new transgenesis platform for Drosophila, named P[acman] that allows them to clone and manipulate very large pieces of DNA and to integrate them at specific genomic sites in the fly genome via ΦC31-mediated integration. They have recently generated two genomic libraries encompassing DNA fragments that average 20 or 80 kb. These libraries will allow unprecedented manipulation of more than 99 percent of the fly genes.
Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.
Luo X, Rosenfeld JA, Yamamoto S, Harel T, Zuo Z, Hall M, Wierenga K, Pastore MT, Bartholomew D, Delgado MR, Rotenberg J, Lewis RA, Emrick L, Bacino CA, Eldomery MK, Coban Akdemir Z, Xia F, Yang Y, Lalani SR, Lotze T, Lupski JR, Lee B, Bellen HJ, Wangler MF, Members of the UDN