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Christian Bökel
Imaging niche signals in the Drosophila germ line
Studying the relation between tissue organization and stem cell niche functionCurrent research
Stem cells are specified and their cell fate maintained by specific microenvironments called stem cell niches. These are defined as regions in a tissue where the signalling millieu is such that a stem cell can keep its properties, specifically including self replication. Hence, the range of the niche growth factor signals defines the physical size of the niche and thus regulates stem cell number.
Our lab is interested in how tissue organization shapes the niches by controlling the spreading of intercellular growth factor signals released by the niche stromal cells. Previous work in several model systems has suggested that adhesion and signalling processes between niche and stem cells are functionally linked. It has therefore been proposed that the tight spatial regulation of niche signaling is achieved via a putative adhesion based “stem cell niche synapse” that however is mechanistically not well defined.
Our lab focuses on the Drosophila germ line, where signalling by the BMP type TGF-beta growth factor Dpp contributes to the niche microenvironment that maintains the germline stem cell (GSC) pool. In the male the Dpp signal is tightly limited to those germline cells in direct contact with the Dpp source. Since Dpp can signal over many cell diameters in other contexts a synapse like mechanism may confine BMP spreading at the niche-GSC interface.
To test this hypothesis we have developed GFP-based live reporters for BMP receptor activation that for the first time allow detection of the active BMP receptor pool live and at subcellular resolution. As predicted by the stem cell synapse hypothesis we could show that in the fly testis BMP signalling is confined to small and discrete subcellular sites at the interface between a single GSC and an underlying BMP secreting niche cell. We will therefore use fly genetics and cell biological methods to perturb niche tissue organisation and functionally dissect this signalling synapse. Currently we are addressing the question of how the directed secretion of BMP growth factors at the niche synapse is achieved, focussing on polarized secretory processes towards the junctions between stem and niche stromal cells. In parallel we are transferring our reporter technology to other signalling pathways known to be involved in niche function, e.g. cytokine signalling via the Jak/Stat cascade.
Beyond stem cell niches, we have begun using biophysical techniques to address general questions of signal transduction with the help of our reporters. We are e.g. interested in the molecular basis for the observed BMP pathway upregulation during mitosis.
Similarly, we hope that fluorescence based receptor activation reporters can help elucidate the basic mechanisms of signal Jak/Stat signal transduction downstream of cytokine receptors which is, compared to other signalling cascades, much less well understood functionally.
The stem cell niche at the fly testis tip. The BMP secreting niche cells of the hub are outlined with FasIII (blue) and germline cells are marked in red. The expression of the Bam-GFP differentiation marker (green) is suppressed in the germline stem cells contacting the hub and the gonioblasts one tier further out.
Future prospects and goals
Working in a Center for Regenerative Therapies we are interested to apply our insights from basic research in clinically relevant systems. While we will continue with the basic science side of our stem cell biology and signal transduction research, we have obtained funding to transfer our methods to mesenchymal stem cells (MSCs). These are acting as stromal cells in the hematopoietic stem cell niche, and can without engrafting augment regenerative responses in unrelated tissue repair paradigms. Instead, the positive effects of MSC application appear to be mediated by intercellular trophic signals.
We will image the communication between MSCs and their target cells to in the long run aid the rational design of MSC based therapies
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Selected publications
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. IF 11,531Bökel 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. IF 6,543
Bökel C, Dass S, Roth S. Drosophila Cornichon acts as cargo receptor for ER export of the TGF-a like growth factor Gurken. Development 2006 Feb; 133(3), 459-70 IF 7,764
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. IF 30,028
Bollenbach T, Pantazis P, Kicheva A, Bökel C, González-Gaitán M, Jülicher F. Precision of the Dpp gradient. Development 2008, 135(6):1137-46. IF 7,293