Our studies of Drosophila embryonic development provide a conceptual framework for studying mammalian developmental systems of cell-cell interaction such as neural tube closure. Characterizing Drosophila genes and their mammalian homologues should greatly enhance our understanding of 1) human embryonic development and 2) the effects that genetic and environmental insults have on development.
We use embryonic dorsal closure in the fruit fly, Drosophila melanogaster, as a model system to study regulated changes in cell shape and motility. During dorsal closure, epidermal cells elongate and lose their continuity with the extraembryonic membrane, the amnioserosa. Epidermis and amnioserosa overlap transiently. The latter is incorporated into the embryo, and the dorsal epidermis achieves closure when the lateral epidermal sheets meet and fuse at the dorsal midline. Clearly, physical changes in cell shape and motility play important roles in this morphogenetic process.
Several of the genes that are required for dorsal closure have recently been cloned and characterized. Molecular studies revealed that although these gene products all function in the dorsal epithelium, they can be separated into at least three groups: I) molecules with structural roles in the maintenance of the integrity of the epithelial sheet; II) molecules that function in Transforming Growth Factor-ß (TGF-ß) -mediated signal transduction, and III) molecules that function in the Jun-N Terminal Kinase (DJNK) signaling pathway.
Our recent progress in identifying Class II gene products and characterizing their roles in TGF-ß-mediated signal transduction provided the first evidence for dual ligand specific TGF-ß receptors. In addition, our research provided the first identification of a transcriptional effector of a TGF-ß signaling pathway. Taken together these data, as well as data from several other laboratories, have led to a sequential signaling model for dorsal closure. After activation by an unknown factor, DJNK. DJNK signaling in leading edge cells induces: 1) elongation of leading edge cells, and 2) secretion of Dpp (Decapentaplegic, a cytokine of the TGF-ß superfamily) from leading edge cells. The Dpp cytokine is postulated to consequently activate Dpp-mediated signaling in adjacent epidermal cells and to induce their elongation.
The primary goals of our research are to build upon our initial observations and extend our knowledge of the molecular mechanisms of dorsal closure. Although many of the components controlling dorsal closure have been identified, several important questions remain unanswered. For example: 1) What signal triggers DJNK signaling? 2) Where is the source of this signal? and even more fundamentally, 3) How are the DJNK and Dpp signals translated into cell shape changes? The objectives of our ongoing research are to answer these three questions.
References to Publications:
VanHook, A. and Letsou, A. (2008) Head Involution in Drosophila: Genetic and morphogenetic connections to dorsal closure. Dev. Dyn. 237:28-38.
Bates, K.L., Higley, M., and Letsou, A. (2008) raw mediates antagonism of AP-1 activity in Drosophila. Genetics 178: 1989-2002.
Scuderi, A. Simin, K, Kazuko, S.G., Metherall, J.E. and Letsou, A. (2006). scylla and charybde, homologues of the human apoptotic gene RTP801, are required for head involution in Drosophila. Dev. Biol. 291:110-22.
Scuderi, A. and Letsou, A. (2005). The Amnioserosa is Required for Dorsal Closure in Drosophila. Dev. Dyn. 232: 791-800. [cover image].
Letsou, A. and Bohmann, D. (2005). Small Flies – Big Discoveries: Nearly a Century of Drosophila Genetics and Development. Dev. Dyn.232: 526-528.
VanHook, A. and Letsou, A. (2004). Bully for Bugs. Dev. Dyn.229: 411-412.
VanHook, A. and Letsou, A. (2003). Closing the gap: Signaling cell shape changes in dorsal closure. Recent Res. Devel. Genet.3: 85-106.
Simin, K., Scuderi, A., Reamey, J. Weiss, R., Metherall, J.E. and Letsou, A. (2002). Profiling patterned transcripts in Drosophila embryos. Genome Res.12:1040-7.
Li, X., Scuderi, A., Letsou, A., Virshup, D.M. (2002). B56-Associated Protein Phosphatase 2A Is Required for Survival and Protects from Apoptosis in Drosophila. Mol. Cell Biol. 22: 3674-84.
Walker, C.S., Shetty, R.P., Clark, K., Kazuko, S.G., Letsou, A., Olivera, B.M., and Bandyopadhyay, P. (2001). On a potential role for vitamin K-dependent γ-carboxylation in animal systems: Evidence for a γ-glutamyl carboxylase in Drosophila.J. Biol. Chem. 276: 7769-74.
Byars, C.L., Bates, K. L., and Letsou, A. (1999). The dorsal-open group gene raw is required for restricted DJNK signaling during closure. Development 126: 4913-23.
Simin, K., Bates, E., Horner, M., and Letsou, A. (1998). Genetic analysis of Punt, a type II Dpp receptor that functions throughout the Drosophila melanogaster life cycle. Genetics 148: 801-813.
Ivanov, I. P., Simin, K., Letsou, A., Atkins, J.F., and Gesteland, R.F. (1998). The Drosophila gene for antizyme requires ribosomal frameshifting for expression and contains an intronic gene for snRNP Sm D3 on the opposite strand. Mol. Cell Biol. 18: 1553-61
Anthea Letsou, Ph.D.
Department of Human Genetics
University of Utah
15 N 2030 E rm. 7160A
Salt Lake City, Utah 84112-5330