Erica M. Selva, Ph.D.
Associate Professor
Selva
Phone: (302) 831-6096
Fax: (302) 831-2281
Email: selva@udel.edu
Office: 325 Wolf Hall
Lab: 348 Wolf Hall
Address:
Department of Biological Sciences
Wolf Hall
University of Delaware
Newark, DE 19716
Education
- B.S. - Cornell University
- Ph.D. - University of Massachusetts Medical School
- Postdoctoral - Harvard Medical School
Teaching
*Course web site available through MyCourses
Research Interests
Studies of signal transduction have yielded a wealth of information about the molecules required to transmit signals from the cell surface to the nucleus. Yet it still remains unknown how a signaling pathway can be differentially modulated to yield unique outcomes from similar cellular contexts. Recently, it has become clear that glycosylation as well as other posttranslational events play a crucial role in the temporal and spatial regulation of signal transmission by altering extracellular receptor-ligand interactions. The objective of my research is to use Drosophila melanogaster as a model system to study the function of posttranslational changes during developmentally critical signaling events.
Drosophila has many advantages: unbiased forward and reverse genetics, extensive genetic tools and a complete genome sequence. It can also serve as a model for human disease pathways because its well-studied signaling pathways are highly conserved. For example, mutations in patched, the Drosophila Hedgehog (Hh) receptor, have been implicated in the most common form of human cancer, basal cell carcinomas, while aberrant Wnt (a Drosophila Wingless (Wg) homolog) expression is linked to breast cancer. My research goals are to identify new components involved in the modification of extracellular signaling molecules as well as to elucidate the function of these molecular changes. Ultimately, I believe this work will cast light on mechanisms by which the extracellular environment might be modified to modulate aberrant signaling activities associated with human diseases.
The 1995 Nobel Prize winning work of Lewis, Nüsslein-Volhard and Wieschaus demonstrated that genetic screening of mutations in Drosophila embryos is an effective method to identify mutations that disrupt specific signaling pathways. Through similar genetic screens new classes of genes have been identified that modulate signaling through posttranslational alteration of the extracellular milieu. These genes can be roughly categorized firstly, as genes that control the modification of extracellular receptors and ligands to regulate their activity and secondly, as genes required for the biosynthesis of extracellular matrix molecules, which in turn regulate the activity of signaling pathways.
One group of genes identified in these embryonic screens are required for the biosynthesis of heparin sulfate (HS) and heparin sulfate proteoglycans (HSPGs). These include sugarless, a UDP-glucose dehydrogenase, sulfateless, an N-deacetylase/N-sulfotransferase (sfl), tout-velu, a glycosyltransferase (ttv) and fringe connection, a nucleotide-sugar-transporter (frc). Despite the fact that these genes are required the biosynthesis of sugar polymers, remarkable signaling pathway selectivity can be ascribed to each. For example, sgl and sfl modulate the activity of the Wg pathway while ttv specifically supports Hh signaling. Indeed, HS and HSPGs have been shown to play important roles in mammalian Wg/Wnt and Fibroblast Growth Factor signaling pathways.
In addition to the HS biosynthetic function of these genes, more specific roles in modifying components of signaling pathways has also been demonstrated. For example, further analysis of Frc has revealed a role for this enzyme in the modification of Notch signaling. The activity of the Notch receptor is modulated by Fng, a glycosyltransferase that catalyzes the elongation of a novel O-linked sugar chain on Notch. This modification enhances Notch responsiveness to the ligand Delta while inhibiting signaling with the alternative ligand Serrate, an exquisite example of a seemly minor posttranslational modification having a profound effect on signaling. Whether Frc supplies the substrate directly for Notch glycosylation or is important of the modification of a factor required for Notch ligand selectivity is question my laboratory will pursue in the future.
Yet another gene identified in this embryonic screen illustrates the importance of posttranslational modification of the signaling activity of secreted ligands. The rasp gene product has been shown to be absolutely required for the signaling activity of Hh. Rasp represents an entirely new class of modifying enzymes, membrane bound acyltransferases, catalyzing the palmitoylation of Hh. Clearly the posttranslational changes necessary to regulate signaling are dynamic, yet the mechanisms by which these alterations modulate signaling remain poorly understood.
Given that these genes play important roles in development and more specifically in regulating signaling, the further elucidation of additional gene products involved in this process in combination with more mechanistic understanding of the roles of the known players will allow us to better understand how the interplay between different cues are regulated developmentally.
Current Projects
- Cloning and Characterization of 7E4, 7H24 and 8J16 - 7E4, 7H24 and 8J16 are three novel mutants identified in embryonic screens for genes involved in posttranslational modification of embryonic signaling. Initial characterization of 7E4 suggests that this gene product is important for the appropriate secretion of the ligand Wg. Each of these genes represents an individual project that will involve the cloning and phenotypic characterization. Once cloned, biochemical characterization of the gene products' activity will be undertaken in order to identify the mechanistic role of these genes in signaling and development.
- Identification of new genes that influence signaling through posttranslational events - A key to understanding the function of a gene is to identify other genes that play a role in the same process. Performing modifier screens using a sensitized genetic background to identify novel genes involved in a process is a powerful tool of Drosophila genetics. For this project novel genetic screens will be developed using known components like Frc and Ttv as well as the genes associated with the novel mutations 7E4, 7H24 or 8J16. A starting point for this project will take advantage of the readily scorable wing phenotype associated with the misexpression of porcupine, an acteytransferase involved in Wg signaling.
- Biochemical characterization of frc and brainiac (brn) in Notch signaling - This project will involve a combined biochemical and genetic approach to elucidate the role of frc and a fringe related glycosytransferase, brainiac (brn), in Notch signaling. This will also entail the development of novel strategies and techniques necessary to dissect the function of these and other gene products with posttranslational phenotypes. These techniques will include the development of a tissue culture model and RNA interference assays.
Research Group
- Yagya Valkya Sharma, Ph.D. - Postdoctoral Researcher (Ph.D., Banaras Hindu University, India). Structural characterization of Sprinter.
- Richard G. Wittmeyer III, B.A. - Research Specialist (B.A., University of Delaware). Functional characterization of Sprinter in Wg/Wnt secretion and signaling.
- Tyler Goralski - Undergraduate Student. Identifying Sprinter protein binding partners within cells.
- Karen Monono - Undergraduate Student. Developing a new method to generate Drosophila germline clone embryos.
- Nicholas Shissias - Undergraduate Student. Examining the function of the O-xylosyltransferase during Drosophila eye development.
- Jessica Torres - Undergraduate Student. Investigating the role of Alg10 in regulated N-glycosylation and Drosophila development.
Selected Publications
- Belenkaya TY, Wu Y, Tang X, et al. The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network. Dev Cell. 2008;14(1):120–131.
- Selva EM, Stronach BE. Germline clone analysis for maternally acting Drosophila hedgehog components. Methods Mol Biol. 2007;397:129–144.
- Goodman RM, Thombre S, Firtina Z, et al. Sprinter: a novel transmembrane protein required for Wg secretion and signaling. Development. 2006;133(24):4901–4911.
- Baeg G-H, Selva EM, Goodman RM, Dasgupta R, Perrimon N. The Wingless morphogen gradient is established by the cooperative action of Frizzled and Heparan Sulfate Proteoglycan receptors. Dev Biol. 2004;276(1):89–100.
- Luders F, Segawa H, Stein D, et al. Slalom encodes an adenosine 3'-phosphate 5'-phosphosulfate transporter essential for development in Drosophila. Embo J. 2003;22(14):3635–3644.
- Micchelli CA, The I, Selva E, Mogila V, Perrimon N. Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling. Development. 2002;129(4):843–851.
- Selva EM, Perrimon N. Role of heparan sulfate proteoglycans in cell signaling and cancer. Adv Cancer Res. 2001;83:67–80.
- Selva EM, Hong K, Baeg GH, et al. Dual role of the fringe connection gene in both heparan sulphate and fringe-dependent signalling events. Nat Cell Biol. 2001;3(9):809–815.
- Selva EM, Maderazo AB, Lahue RS. Differential effects of the mismatch repair genes MSH2 and MSH3 on homeologous recombination in Saccharomyces cerevisiae. Mol Gen Genet. 1997;257(1):71–82.
- Selva EM, New L, Crouse GF, Lahue RS. Mismatch correction acts as a barrier to homeologous recombination in Saccharomyces cerevisiae. Genetics. 1995;139(3):1175–1188.
- Selva E, Raden DL, Davis RJ. Mitogen-activated protein kinase stimulation by a tyrosine kinase-negative epidermal growth factor receptor. J Biol Chem. 1993;268(3):2250–2254.
