Research
The Bischoff lab is interested in how shape and form arise during development. Ultimately, it is the behavior of individual cells, such as cell migration and cell shape change, that underlies the formation of tissues and organs. We aim to understand how cells interpret information to implement different cell behaviours and how different behaviours are coordinated. Furthermore, we study how signalling is transduced into specific activities of the cytoskeleton and how different cytoskeletal activities are coordinated to execute a certain behaviour.
Gaining insights into the (mis-) regulation of cell behavior, such as cell migration, is essential to unravel the mechanisms behind medically important processes (such as wound healing and numerous diseases, ranging from cleft palate to cancer). During wound healing, for example, epithelial cells start migrating to close the wound, and during tumour progression, cancer cells become mobile and form metastases.
Morphogenesis of the adult abdominal epidermis of Drosophila
In order to investigate the regulation and coordination of cell behaviour, we study the formation of the adult abdominal epidermis of Drosophila. This epithelium is newly formed during metamorphosis, as the migrating and proliferating adult progenitor cells (histoblasts) replace the larval epithelial cells (LECs), which undergo apoptosis. This epithelium represents a powerful model to study different cell behaviours during morphogenesis and is easily accessible for live imaging.
Image: Morphogenesis of the abdominal epidermis of Drosophila. The small histoblasts replace the large larval epithelial cells during metamorphosis. Cells are labelled with Histone-GFP.
In vivo 4D microscopy
To study cell behaviours, we use in vivo 4D microscopy. This technique allows us to film morphogenesis in vivo, followed by a detailed analysis of the behaviour of all the cells involved using software tools (e.g. calculating 3D representations, cell trajectories and cell division orientation). Furthermore, the sophisticated genetic tools available in Drosophila permit experimental manipulation of this system and the identification of relevant genes.
Image: 3D representation of histoblasts that move towards the dorsal midline during abdominal morphogenesis (Bischoff and Cseresnyes, 2009).
Migration of an epithelial sheet
4D analysis of the abdomen has enabled us to gain some fundamental insights into how histoblasts behave during abdominal development. We found that extensive cell migrations contribute most to morphogenesis in the abdomen, whereas cell division orientation and local rearrangements of cells are seem to be of less importance (Bischoff and Cseresnyes, 2009).
Image: Morphogenesis of the abdominal epidermis of Drosophila. The small histoblasts replace the large larval epithelial cells during metamorphosis. Cells are labelled with Cadherin-GFP.
Cell migration and apical constriction
Moreover, we have shown that the LECs also display complex behaviour, an important aspect of which is that they become mobile and migrate directionally (Bischoff, 2012). During this process, LECs undergo a transition from stationary to migratory behaviour. While the LECs are migrating, they also constrict apically. We found that the activity of the small GTPase Rho1 biases LECs towards apical constriction (high Rho1 activity) or migratory behaviour (low Rho1 activity). Furthermore, the planar polarity of the larval epithelium is responsible for the initial orientation of LEC migration.
Image: Larval epithelial cells migrating during morphogenesis of the adult abdominal epidermis. Cells are labelled with GMA (Bischoff, 2012).
Morphogen transport during development
We are also interested how signalling molecules are transported from one cell to the next. In collaboration with Isabel Guerrero (Centro de Biología Molecular, Madrid), we have recently shown that the establishment of the Hedgehog (Hh) morphogen gradient depends on the transport of Hh along long filopodia-like protrusions, called cytonemes (Bischoff et al., 2013). We used in vivo imaging in the abdomen to show that cytonemes can be observed in the unperturbed living organism and that the establishment of the morphogen gradient correlates with cytoneme formation in space and time.
We also showed in wing imaginal discs that shortening cytonemes by manipulating the cytoskeleton leads to a shortening of the morphogen gradient. Overall, this represents an important step towards understanding the establishment of morphogen gradients and the contribution of morphogen transport via cytonemes.
Image: Hedgehog activity gradient (left) and cytonemes (right) in histoblasts. Gradient is labelled with Ptc-trap-GFP and cytonemes are labelled with Ihog-RF (Bischoff et al., 2013).