Research: Cell fate control in vertebrate development
The aim of my lab's research is to understand how cells acquire their fates during development. As principal model, we use the zebrafish (Danio rerio) to investigate the cell fate control of mesodermal lineages. Our work combines transgenic, genome editing, cross-species analysis of cis-regulatory elements, and latest imaging techniques to elucidate:
a) Lateral plate mesoderm (LPM): origins, emergence, and its descendant organs;
b) Mechanisms of chordoma formation and related mesodermal tumors.
Lateral Plate Mesoderm: the forgotten mesoderm
In vertebrates, the organ precursors for the heart, blood, endothelium, kidney, and limbs arise in close proximity from distinct territories within the LPM at the periphery of the embryo. The principles driving the LPM into its dramatically different cell fates must be of ancient evolutionary origin. The molecular mechanisms that divide lateral territories along the embryonic axis into their different organ cell fates remain nonetheless poorly understood. More in-depth knowledge about the mechanisms of cell fate control is critical to our understanding of vertebrate evolution, to therapeutic drug discovery, and to improve the targeted manipulation of embryonic stem (ES) or induced pluripotent stem (iPS) cells into sought-after regenerative cell types.
Our experiments apply spatio-temporally controlled lineage tracing and genetic perturbations via Tamoxifen-inducible Cre/lox transgenics and CRISPR-Cas9 genome editing to elucidate the mechanisms of earliest cardiovascular and general LPM lineage patterning. For imaging, we routinely apply SPIM/lightsheet imaging to capture the developing embryo in toto. Parallel approaches apply discovery of novel cis-regulatory elements, functional studies of novel candidate genes, and live imaging to identify novel molecular components of LPM patterning and its descendant cell lineages.
We combine our zebrafish work with reporter assays in chick embryos and in collaboration also expand our studies to other model systems. We also continue to refine genetic lineage tracing techniques and genome engineering in the zebrafish.
Mechanisms of chordoma formation and mesodermal tumors
Chordoma is a rare, slow-growing tumor that arises from remnant cells of the notochord, a collagen-secreting embryonic structure that normally regresses before birth. Treatment remains difficult due to the delicate surgical removal and radiation/chemo resistance of chordoma. Chordoma genomes predominantly feature deletions and amplifications, including of the T/Brachyury gene and of several RTK loci; the causative impact of these mutations remains undetermined. Brachyury is a developmental T-box transcription factor that drives mesodermal cell fates and EMT. Its expression is controlled by an incompletely charted program that includes feedback loops with RTK/Ras-relayed pathways. The lack of a suitable genetic model has previously hampered efforts to study the genetic causes, the mechanisms of tumor onset, and effective therapeutic interventions.
Our chordoma and cancer endeavors are led by Dr. Alexa Burger in the lab. To study chordoma in vivo, we leverage our expertise in transgenic tumor modelling and our recently established first animal model for chordoma in zebrafish. The zebrafish embryo provides a potent model for chordoma formation: zebrafish chordomas rapidly form within 3-5 days in developing notochord cells upon oncogenic transformation. The resulting tumors share extensive histo-pathological features with human chordoma, providing a potent platform for genetic and chemical compound testing. By combining transgenic and genome editing approaches, we now aim to clarify the unknown tumorigenic mechanisms in chordoma and other secretory cell-based cancers.
- since Spring 2013:
SNSF/SNF Assistant Professor, IMLS, UZH; Zürich, Switzerland.
Postdoctoral research fellow with Leonard Zon, MD, HHMI/Boston Children's Hospital/Harvard Medical School; Boston, USA.
EMBO Long-term Fellowship (2008-2009).
HFSP Long-term Fellowship (2009-2012).
SNSF/SNF Advanced Researcher Fellowship (2012-2013).
NIH NI-DDK K99/R00 (2012).
Ph. D. in Molecular Biology, with Konrad Basler, PhD, Instute of Molecular Biology, UZH; Zürich, Switzerland.
Diploma in Molecular Biology, Biochemical Immunology, Chemical Physics, UZH; Zürich, Switzerland.