The vertebrate body grows from the neck down by the progressive addition of cells from a mesodermal progenitor population located at the most posterior end of the embryo. A major interest in the lab is to understand the mechanisms that regulate this process. Our focus is on the signaling factors that pattern and sustain the mesodermal progenitors, including Nodals, Wnts, Fgfs and Bmps, and their interaction with transcription factors that regulate the progenitors, particularly members of the T-box family. For example (Szeto and Kimelman, 2006), we demonstrated that the position of the mesodermal progenitors along the body is regulated by a combination of Nodal and Bmp signals, which regulate a clock that tells the mesodermal progenitors when to commit to differentiation. We showed (Martin and Kimelman, 2008) that an autoregulatory loop involving the Brachyury transcription factors (No tail and Bra) and the Wnt signaling factors is required to maintain the mesodermal progenitors during the early stages of development. Our current research involves the production of transgenic zebrafish that will allow us to understand how the fate and proliferation of the mesodermal progenitors is regulated.
During gastrulation, the vertebrate embryo undergoes dramatic morphological changes to form the final body plan. One of these morphological transformations involves a process called convergence & extension, which moves the mesodermal cells into their final position in the embryo. We recently (Weiser et al., 2007) found that a scaffolding protein called Gravin regulates a major change in the cells from convergence (migratory behavior) to extension (intercalative behavior). When the cells lack Gravin, they fail to suppress a particular type of protrusive activity called blebbing, which is important for cell migration; it is this failure to shut down blebbing in the absence of Gravin that prevents embryo extension, resulting in a deformed body. These results have interesting implications not only for development, but also for metastasis since Gravin is implicated as a tumor suppressor. We are currently working to understand how Gravin is regulated, and to identify the mechanism by which Gravin suppresses blebbing in the early embryo.
Together with Wenqing Xu (Biostructure Department), we have been taking a structural approach to understanding the Wnt signaling pathway, which plays major roles in embryonic development, stem cell maintenance and disease. We use X-ray crystallography to examine the interactions between different proteins in this pathway, and then follow up these studies with various biochemical and embryological analyses. From these studies we have developed a model for the regulation of the key mediator of this pathway, b-catenin, by a complex of proteins known as the Destruction Complex. We are continuing our analysis of this pathway.
Bjornson, C., Griffin, K., Farr, G.H.I., Terashima, A., Himeda, C., Kikuchi, Y., and Kimelman, D. (2005). Eomesodermin is a localized maternal determinant required for endoderm induction in zebrafish. Dev Cell 9, 523-533.
Kimelman, D., and Xu, W. (2006). The b-catenin destruction complex: Insights and questions from a structural perspective. Oncogene 25, 7482-7491.
Sampietro, J., Dahlberg, L., Cho, U.S., Hinds, T.R., Kimelman, D., and Xu, W. (2006). Crystal structure of a b-catenin/BCL9/Tcf4 complex. Mol Cell 24, 293-300.
Szeto, D.P., and Kimelman, D. (2006). The regulation of mesodermal progenitor cell commitment to somitogenesis subdivides the zebrafish body musculature into distinct domains. Genes Dev 20, 1923-1932.
Webb, A.E., Sanderford, J., Frank, D., Talbot, W.S., Driever, W., and Kimelman, D. (2007). Laminin a5 is essential for the formation of the zebrafish fins. Dev Biol 311, 369-382.
Weiser, D.C., Pyati, U., and Kimelman, D. (2007). Gravin regulates mesodermal cell behavior changes required for axis elongation during zebrafish gastrulation. Genes Dev 21, 1559-1571.
Martin, B.L., and Kimelman, D. (2008). Regulation of canonical Wnt signaling by Brachyury is essential for posterior mesoderm formation. Dev Cell 15, 121-133.
Webb, A.E., Driever, W., and Kimelman, D. (2008). psoriasis regulates epidermal development in zebrafish. Dev Dynamics 237, 1153-1164.
Revised 12/15/2008