Previous and Current Research

Stem cells are essential for tissue formation during development, and allow tissue maintenance and repair during the adult life of an organism. However, stem cell identity, survival, and activity are not intrinsic properties that stem cells possess once they are specified. Instead, these stem cell properties are in many cases first induced and then maintained by a specific microenvironment termed niche, in which instructive or permissive signals emanate from tissues surrounding the stem cell population and affect its behavior. Thus, the range with which these signals spread in the tissue sets the physical size of the stem cell niche and the numerical size of the stem cell pool. To improve our understanding of how stem cell niches function at the molecular, subcellular, and tissue level we use the germ line stem cell (GSC) niche of the fruit fly Drosophila as a model system. Our key question is how tissue organization controls the range of the stem cell signals and therefore niche size.

In the fly testis, GSC fate is maintained through suppression of the germ line differentiation factor Bam in response to a niche signal emanating from the somatic niche cells thatvis mediated by the bone morphogentic protein (BMP) family growth factor Dpp. Interestingly, only GSCs in immediate contact with the signal producing somatic cells are able to receive this niche signal, although BMPs act as archetypal long range signalling factors in other contexts.

To study how this range restriction is achieved we have developed a a fluorescent reporter for BMP receptor activation that allows us to track the niche signalling events live and with subcellular resolution. Our reporter us based on a conformationally sensitive GFP derivative fused to the Drosophila type I BMP receptor Thickveins. In the inactive state, its fluorescence is switched off by interaction of the receptor with an endogenous inhibitor protein called FKBP12. Receptor activation displaces FKBP12 and allows the GFP moiety fused to the receptor to adopt a fluorescent conformation. With the help of this reporter we could show that transduction of the niche signal is confined to adherens junctions between niche and germ line cells, limiting the ability of the ligand to spread through the tissue.

This spatially confined signalling is achieved by local release of the ligands at the junctions, and we could demonstrate that this achieved by a shared use of the secretory machinery targetting Cadherins to the junctions.

We have since started to adapt our reporter technology to image the activation state of components of other signalling pathways, e.g. the Hh and Jak/Stat pathways, that have also been implicated in stem cell niche function.

In addition, we study these niche pathways using biophysical tools including fluorescence correlation spectroscopy, addressing questions like ligand-ECM affinities or receptor preclustering.

Future Prospects and Goals

Stem cells are at the core of the expanding field of regenerative medicine. However, culturing tissue specific stem cells is still a major technical problem limiting the application of this exciting therapeutic approach. In part these problems are caused because our culture conditions fail to mimic the conditions under which stem cells thrive in their natural environment. Understanding how a model stem cell niche works at the molecular and tissue level will therefore be of interest beyond the field of fly developmental biology, especially as the same signalling cascades have been implicated in regulating bone marrow and neuronal stem cells, which are of obvious clinical interest. In the long run our results may aid the design of stem cell culture systems mimicking natural niches by providing the required signals in the appropriate spatial and temporal organization.

Group Members

List of group members

Selected Publications

Bollenbach T, Pantazis P, Kicheva A, Bökel C, González-Gaitán M, Jülicher F. Precision of the Dpp gradient. Development. 2008 Mar;135(6):1137-46.

Bökel, C. EMS Screens: From Mutagenesis to Screening and Mapping. In: Dahmann, C. (ed.), 2008, Methods in Molecular Biology: Drosophila. pp119-138. Humana Press, Totowa, NJ

Bökel C, Schwabedissen A, Entchev E, Renaud O, and González-Gaitán M. Sara endosomes and the maintenance of Dpp signaling levels across mitosis. Science 2006, Nov; 314 (5802): 1135-39

Bökel C, Dass S, Roth S. Drosophila Cornichon acts as cargo receptor for ER export of the TGF α-like growth factor Gurken. Development 2006 Feb; 133(3), 459-70

Bökel C, Prokop A, Brown NH. Piopio and Papillotte, Drosophila ZP domain proteins required for cell adhesion to the apical extracellular matrix and microtubule organization. J Cell Sci 2005 118: 633-42.

Bökel C, Brown NH. Integrins in development: moving on, responding to, and sticking to the extracellular matrix. Dev Cell. 2002 Sep;3(3):311-21.

Peri F, Bökel C, Roth S. Local Gurken signaling and dynamic MAPK activation during Drosophila oogenesis.  Mech. Dev. 1999 Mar;81(1-2):75-88. (shared first authorship)