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STUART J. NEWFELD Associate Professor Ph.D., 1992, Emory University Send e-mail to newfeld@asu.edu

Molecular Genetics and Genomics; Intercellular Signaling in Development and Cancer

Intercellular signaling coordinates the development of every cell required to form a mature organism. Secreted molecules of the Transforming Growth Factor-beta (TGF-beta) superfamily contribute to proper development in a wide range of species, including humans. I would like to understand how TGF-beta signals affect cell growth and differentiation. My research utilizes a multidisciplinary approach in a model organism, the fruit fly Drosophila melanogaster. In Drosophila, several proteins of the TGF-beta family influence cell fate decisions and cell proliferation at numerous stages of embryonic development. Several of the molecules responsible for communicating the instructions contained in TGF-beta signals from the cell surface to the nucleus of target cells have been identified. These include a variety of transmembrane receptors and the cytoplasmic proteins MAD and MED. In addition, MAD and MED belong to a new family of tumor suppressor genes (the Smad family) implicated in numerous cancers.

We are currently conducting three research projects. First, we are using molecular genetics to investigate the effect of multiple signaling pathways on the expression of the TGF-beta family member decapentaplegic (dpp) during embryonic development. Second, we conducted a classical genetic screen to identify new components of the dpp signaling pathway and we are analyzing genes identified in this screen. Third, we are using transgenic methods to study six human genes related to MAD as well as mutant alleles of these genes that were isolated from human tumors. We hope to identify the mechanisms by which these mutant genes cause cancer. These studies are funded by NIH.

Selected Publications

Drosophila Comparative Genome Sequencing and Analysis Consortium (2007) Genomics on a phylogeny: evolution of genes and genomes in the genus Drosophila. Nature (submitted, 7/19/07).

Takaesu, N.T, Bulanin, D., Orenic, T. & Newfeld, S.J. (2007) A combinatorial enhancer recognized by Mad, TCF and Brinker first activates then represses dpp expression in the posterior spiracles of Drosophila. Dev. Biol. (accepted pending revision, 6/5/07).

Hudson, S.G., Garrett, M., Carlson, J., Micklem, G., Celniker, S., Goldstein, E.S. & Newfeld, S.J. (2007) Phylogenetic and genome-wide analyses suggest a functional relationship between kayak the Drosophila Fos homolog and fig a predicted PP2C phosphatase nested within a kayak intron. Genetics (in press October, doi: 10.1534/genetics.107.071670).

Johnson, A.N., Burnett, L., Sellin, J. Paululat, A. & Newfeld, S.J. (2007) Defective Dpp signaling results in heart overgrowth and reduced cardiac output in Drosophila. Genetics 176:1609-1624.

Takaesu, N.T., Hyman-Walsh, C.A., Ye, S., Wisotzkey, R.G., Stinchfield, M.J., O'Connor, M.B., Wotton, D.& Newfeld, S.J.(2006) dSno facilitates Baboon signaling in the Drosophila brain by switching the affinity of Medea away from Mad and toward dSmad2. Genetics (174:1299-1313).

Newfeld, S. J. & Wisotzkey, R.G. (2006) Molecular Evolution of Smad Proteins. In Smad Signal Transduction, Eds. C. Heldin, & P. ten Dijke, Springer, Netherlands, pp. 15-35.
-- Invited Chapter One and the Cover Illustration for the first book on the Smad Family.

Takaesu, N.T., Herbig, E.J., Zhitomersky, D., O'Connor, M.B. & Newfeld, S.J. (2005) DNA-binding domain mutations in Smad genes yield dominant negative proteins or a neomorphic protein that can activate Wg target genes in Drosophila. Development 132:4883-4894.

Hyman, CA, Bartholin, L, Newfeld, SJ and Wotton, D (2003) Drosophila TGIF proteins are transcriptional activators. Molecular and Cellular Biology 23:9262-9274.

Johnson, A.N. Bergman, C., Kreitman, M. & Newfeld, S.J. (2003) Embryonic enhancers in the dpp disk region regulate a second round of Dpp signaling from the dorsal ectoderm to the mesoderm that represses Zfh-1 expression in a subset of pericardial cells. Developmental Biology 262:137-151.

Wisotzkey, RG, Johnson, AN, Takaesu NT and Newfeld, SJ (2003) a/b hydrolase2, a predicted gene adjacent to Mad in Drosophila melanogaster, belongs to a new global multigene family and is associated with obesity. Journal of Molecular Evolution 56:351-361.

Kumar, S, Jayaraman, K, Panchanathan, S, Gurunathan, R, Marti-Subirana, A and Newfeld, SJ (2002) BEST: A novel computational approach for comparing gene expression patterns from early stages of Drosophila melanogaster development. Genetics 162:2037-2047.

Kumar, S and Newfeld, SJ (2002) Review of Modern Genetic Analysis by A. J. Griffiths, W. M. Gelbart, R. C. Lewontin and J. H. Miller. Quarterly Review of Biology 77:456-457.

Takaesu, NT, Johnson, AN and Newfeld, SJ (2002) Posterior spiracle specific GAL4 lines: New reagents for developmental biology and respiratory physiology. genesis: The Journal of Genetics and Develoment 34:16-18.

Takaesu, NT, Johnson, AN, Sultani, OH and Newfeld, SJ (2002) Combinatorial signaling by an unconventional Wg pathway and the Dpp pathway requires Nejire (CBP/p300) to regulate dpp expression in posterior tracheal branches. Developmental Biology 247:225-236.

Newfeld, SJ and Takaesu, NT (2002) An analysis using the hobo genetic system reveals that combinatorial signaling by the Dpp and Wg pathways regulates dpp expression in leading edge cells of the dorsal ectoderm in Drosophila melanogaster. Genetics 161:685-692.

Johnson, AN and Newfeld, SJ (2002) The TGF-beta family: signaling pathways, developmental roles and tumor suppressor activities. TheScientificWorldJournal 2: 885-918. 

Waldrip, WR, Takaesu, NT and Newfeld, SJ (2001) Identification of blue balancers and mutant collections compatible with hobo element transgenes. Dros. Inf. Serv. 84:169-172.

Marquez RM, Singer MA, Takaesu NT, Waldrip RW, Kraytsberg Y, Newfeld SJ (2001) Transgenic analysis of the Smad family of TGF-beta signal transducers suggests new roles and new interactions between family members. Genetics 157:1639 -1648.

Su MA, Wisotzkey RG, Newfeld SJ (2001) A screen for modifiers of decapentaplegic mutant phenotypes identifies lilliputian, the only member of the Fragile-X/Burkitt's Lymphoma family of transcription factors in Drosophila melanogaster. Genetics 157:717-725.

Jockusch E, Nulsen C, Newfeld SJ, Nagy LM (2000) Leg development in flies vs. grasshoppers: differences in dpp expression do not lead to differences in the expression of downstream components of the leg patterning pathway. Development 127:1617-1626.

Newfeld SJ, Wisotzkey RG, Kumar S (1999) Molecular evolution of a developmental pathway: phylogenetic analyses of TGF-beta family ligands, receptors and Smad signal transducers. Genetics 152:783-795.

Newfeld SJ, Takaesu NT (1999) Local transposition of a hobo element within the decapentaplegic locus of Drosophila. Genetics 151:177-187.