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The Korswagen group combines new methods in gene expression analysis with model organism genetics to investigate molecular mechanisms in developmental biology.
We focus on the genetic pathways that control cell fate determination and cell migration. As part of our research, we are developing new methods for multidimensional gene expression analysis. As a model, we use Caenorhabditis elegans. This small nematode offers a powerful genetic system to understand evolutionarily conserved mechanisms with single cell resolution in vivo.
Wnt signaling plays a central role in embryonic development, adult tissue homeostasis and cancer. At the cellular level, Wnt proteins can trigger a variety of responses, ranging from cell fate specification and proliferation, to cell polarization and migration. We are interested in the canonical and non-canonical signaling mechanisms that mediate these different responses. We focus on the Wnt dependent migration of the Q neuroblast descendants to address questions on the role of Wnt signaling in cell migration, the mechanism of canonical and non-canonical Wnt signaling, and cross-talk between Wnt pathways. In our toolkit, we have methods for time-lapse confocal imaging, quantitative in vivo gene expression analysis (smFISH), FACS based cell sorting for mRNA sequencing, and CRISPR/Cas9 mediated genome editing.
During embryogenesis, a single fertilized oocyte generates the wide range of specialized cell types that make up all the different tissues and structures of the complete organism. Central to this differentiation process is the activation and inhibition of specific genes, which enables cells to adopt distinct fates. We use the C. elegans Q neuroblast lineage as a model to study which changes in gene expression lead an epidermal cell to differentiate into three specialized neurons. We have developed single cell mRNA sequencing approaches to examine gene expression dynamics during Q lineage progression. Moreover, as part of an NWO (ENW GROOT) funded consortium, we are generating new methods for probing transcription factor binding and epigenetic chromatin states at the single cell level.
The complexity of the genetic programs that drive cellular specialization and physiology requires genome-wide analysis of gene expression patterns. With its relatively simple and invariant anatomy, C. elegans is ideal for high resolution gene expression analysis, providing a powerful platform for connecting spatial information to specific cellular functions. We have developed a tomo-seq method for C. elegans to obtain genome-wide expression data with spatial information. By cryo-sectioning animals and performing mRNA sequencing on individual sections, we can generate high-resolution expression maps that closely reproduce known expression patterns at near cellular resolution. When applied to mutants or different growth conditions, this method provides a powerful new approach to discover organ, tissue, or even single cell changes in gene expression. We are using this method to study a broad range of topics, such as spatial gene expression dynamics during development, tissue-specific transcriptional effects of lifespan pathways, evolutionary conservation of gene expression patterns, and interactions of parasitic nematodes with their plant hosts.
Mentink RA, Middelkoop TC, Rella L, Ji N, van Oudenaarden A, Korswagen HC.
Harterink M, Port F, Lorenowicz M, McGough I, Silhankova M, Betist M, van Weering J, van Heesbeen R, Middelkoop T, Basler K, Cullen P, Korswagen HC.
See also: News & Views Highlight in EMBO J
Essers MA, de Vries-Smits LMM, Barker N, Polderman PE, Burgering BMT, Korswagen HC.
Ji N, Middelkoop TC, Mentink RA, Betist MC, Tonegawa S, Mooijman D, Korswagen HC*, van Oudenaarden A*
*Joint senior/corresponding authors. See also: Cell video abstract
Yang PT, Lorenowicz M, Silhankova M, Coudreuse DYM, Betist MC, Korswagen HC.
Coudreuse DYM, Roel G, Betist MC, Destree O, Korswagen HC.
Rik Korswagen is a group leader at the Hubrecht Institute and professor of Molecular Developmental Genetics at Utrecht University. His group is interested in the mechanism of Wnt signal transduction in development and disease and uses the C. elegans model system to study Wnt signaling at single cell resolution. His current research focuses on canonical and non-canonical Wnt signaling mechanisms in cell migration, which he studies using a combination of genetics, time-lapse confocal imaging, RNA sequencing and single molecule mRNA in situ hybridization.
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