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. Stem cell identity, survival, and activity are not intrinsic properties once they are specified. Instead, they are 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.

Signalling by the TGF- βtype ligand Dpp from somatic cells at the tip of the male and female Drosophila gonad represses the bag-of-marbles (bam) gene in the GSCs. Bam expression is found in early, committed germ cells and has been shown to be sufficient to drive this differentiation. Activation of the Dpp pathway and corresponding repression of Bam thus demarcates the GSC niche, which is defined as the region where a stem cell can keep its properties.

Interestingly, male and female gonads differ in the shape and range of Dpp signalling activity and the resulting pattern of Bam repression. As might be expected for a secreted growth factor, in the female gonad the Dpp signal appears to spread through the niche region in a graded fashion, and Bam repression is gradually relieved over a distance of around three cell diameters from the source of Dpp. In contrast, in the male only the GSCs in immediate contact with the somatic cells secreting Dpp receive the signal and respond by turning off Bam.

Preliminary evidence from other tissues suggests that in epithelia Dpp and its receptors are targeted to intercellular contact sites. These junctions may therefore form signalling synapses where signalling molecules become confined and signal transduction can occur at increased local concentrations. Since there are striking differences in tissue organization and junctional arrangement between the GSC and somatic support cells in the male and female niche we want to test through a comparative approach how tissue organization is related to the threedimensional shaping of the niche signal.

We are therefore currently developing imaging tools such as fluorescence based reporter constructs that will allow us to selectively detect activated Dpp receptors with subcellular resolution. These advanced imaging methods will ideally complement the powerful genetical and cell biological methods already available in this well studied model of a stem cell niche.

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 TGF-ß 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)