Areas of Research: Cell Biology, Computation & Modeling, Development, Genetics
- Molecular Biology and the Lewis-Sigler Institute for Integrative Genomics
435 Moffet Laboratory
In the late 1970s, Eric Wieschaus and Christiane Nüsslein-Volhard carried out large-scale mutagenesis screens to identify genes controlling embryonic development in Drosophila. In contrast to previous genetic analyses, these screens were designed for genomic saturation, i. e.; identifying key components in all pathways govern gross morphology, patterning and differentiation. These experiments established a basic “tool box” of maternal factors and signaling pathways that operate in the Drosophila embryo and are in fact conserved with remarkable fidelity in all multicellular organisms. Mutations in the associated genes account for a significant fraction of inherited birth defects in humans and play a major role in cancer. Wieschaus and collaborators then went on to elucidate basic features of the Wnt pathway, showing for example, that Wnt signaling modulates levels and nuclear localization of beta-catenin (=Armadillo) and investigating the role of GSK3b and APC in that process. More recent work has focused on the cell biological mechanisms that control cell shape change and movement during gastrulation, and on quantitative biophysical measurements of morphogen gradients during early development. Wieschaus is a HHMI investigator, a member of the National Academy of Sciences (USA), a foreign member of the Max Planck Society, and the 1995 Nobel Laureate for Medicine.
Embryonic development of Drosophila melanogaster
We are interested in the patterning that occurs in the early Drosophila embryo. Most of the gene products used by the embryo at these stages are already present in the unfertilized egg and were produced by maternal transcription during oogenesis. A small number of gene products, however, are supplied by transcription in the embryo itself. We have focused on these "zygotically" active genes because we believe the temporal and spatial pattern of their transcription may provide the triggers controlling the normal sequence of embryonic development.
The earliest requirements for zygotic gene activity become apparent at cellularization. The early cleavage divisions in Drosophila involve nuclear mitoses without intervening cytokinesis. Ultimately, they produce a syncytial blastoderm of 6,000 nuclei. "Cellularization" of these nuclei requires a massive, rapid reorganization of the embryonic cytoskeleton that occurs after the 13th cleavage cycle. This reorganization is blocked by inhibitors of RNA synthesis such as a-amanitin. By screening a collection of chromosomal deletions that span the entire Drosophila genome, we identified those zygotically active loci required at different stages during cellularization. In embryos deficient for three of these genes, the hexagonal arrays of F-actin required to pull plasma membrane down between adjacent nuclei are abnormal, and multiple nuclei are enclosed into single cells. Other loci affect cytoplasmic clearing, membrane synthesis, and the morphology of contractile rings. We have cloned several of these genes and have characterized their role in restructuring the embryonic cytoskeleton. We have also begun analysis of the role of microtubule- based transport in the early embryo, using optical traps and image enhancement to measure forces and kinetic behaviors of individual cellular organelles. Once the embryo has completed cellularization, it begins gastrulation. A ventral furrow and posterior midgut are formed by characteristic changes in cell shape that occur only in the ventral and posterior regions of the embryo. Our analysis has concentrated on genes (folded gastrulation [=fog] and concertina [= cta]) that are required for the process. Using genetic mosaics, we have shown that fog+ expression is required zygotically and only in specific regions of the embryo. Cta expression is required in the maternal germ line, and its RNA is uniform throughout the egg. The surprising homology of the cta gene product to G protein a-subunit argues for cell signaling process coordinating cell shape changes in each invagination.
We are also interested in how complex patterns of cell differentiation are established within epithelial cells at later stage of development. In Drosophila, maintenance of segmental pattern requires interactions between groups of cells that express different "segment polarity" genes. Our work has shown that changes in Armadillo protein levels are among the earliest responses to the intracellular signals that control patterning. Armadillo encodes the Drosophila homologue of §-catinin, a major component of vertebrate adhesive junctions. The proteins that regulate its expression in Drosophila are homologues of vertebrate proteins (Wnt-1, APC) that have been implicated in many forms of human cancer. We are using a variety of molecular and genetic strategies in Drosophila to determine how these genes interact with Armadillo to produce changes in cell morphology and behavior.
- Khan Z, Wang YC, Wieschaus EF, Kaschube M. (2014) Quantitative 4D analyses of epithelial folding during Drosophila gastrulation. Development. Pubmed
- He B, Doubrovinski K, Polyakov O, Wieschaus E. (2014) Apical constriction drives tissue-scale hydrodynamic flow to mediate cell elongation. Nature. 508: 392-96. Pubmed
- Dubuis JO, Tkacik G, Wieschaus EF, Gregor T, Bialek W. (2013) Positional information, in bits. Proc Natl Acad Sci. 110: 16301-08. Pubmed
- Wang YC, Khan Z, Wieschaus EF. (2013) Distinct Rap1 activity states control the extent of epithelial invagination via α-catenin. Dev Cell. 25: 299-309. Pubmed
- Osterfield M, Du X, Schüpbach T, Wieschaus E, Shvartsman SY. (2013) Three-dimensional epithelial morphogenesis in the developing Drosophila egg. Dev Cell. 24: 400-10. Pubmed
- Di Talia S, She R, Blythe SA, Lu X, Zhang QF, Wieschaus EF. (2013) Posttranslational control of Cdc25 degradation terminates Drosophila's early cell-cycle program. Curr Biol. 23: 127-32. Pubmed
- Gelbart MA, He B, Martin AC, Thiberge SY, Wieschaus EF, Kaschube M. (2012) Volume conservation principle involved in cell lengthening and nucleus movement during tissue morphogenesis. Proc Natl Acad Sci. 109: 19298-303. Pubmed
- Grimm O, Zini VS, Kim Y, Casanova J, Shvartsman SY, Wieschaus E. (2012) Torso RTK controls Capicua degradation by changing its subcellular localization. Development. 139: 3962-68. Pubmed
- Drocco JA, Wieschaus EF, Tank DW. (2012) The synthesis-diffusion-degradation model explains Bicoid gradient formation in unfertilized eggs. Phys Biol. 9: 055004. Pubmed
- He B, Caudy A, Parsons L,...Wieschaus E. (2012) Mapping the pericentric heterochromatin by comparative genomic hybridization analysis and chromosome deletions in Drosophila melanogaster. Genome Res. 22: 2507-19. Pubmed
- Di Talia S, Wieschaus EF. (2012) Short-term integration of Cdc25 dynamics controls mitotic entry during Drosophila gastrulation. Dev Cell. 22: 763-74. PubMed
- Wang YC, Khan Z, Kaschube M, Wieschaus EF. (2012) Differential positioning of adherens junctions is associated with initiation of epithelial folding. Nature. 484: 390-93. PubMed
- Drocco JA, Grimm O, Tank DW, Wieschaus E. (2011) Measurement and perturbation of morphogen lifetime: effects on gradient shape. Biophys J. 101: 1807-15. PubMed
- Little SC, Wieschaus EF. (2011) Shifting patterns: merging molecules, morphogens, motility, and methodology. Dev Cell. 21: 2-4. PubMed
- Little SC, Tkačik G, Kneeland TB, Wieschaus EF, Gregor T. (2011) The formation of the bicoid morphogen gradient requires protein movement from anteriorly localized mRNA. PLoS Biol. 9: e1000596. PubMed
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