Stem cells in adult tissues are viewed as products of their microenvironment or niche. Although the signaling pathways involved in the interaction of stem cells with niche have been identified in many stem cell populations, the mechanisms of how stem cells and their specialized sisters differentially respond to the signals from niche remain poorly understood.

Researchers at Institute of Zoology, Chinese Academy of Sciences and Tsinghua University, used Drosophila germline stem cells(GSCs) as a model to explore the mechanism of how GSC and cystoblast cells differentially respond to the niche signals. Previous studies have demonstrated that the niche signal (i.e. BMP)-dependent transcriptional silencing of the bam gene, which encodes the key GSC/CB differentiation-promoting factor, is essential for the maintenance of GSCs. Remarkably, bam transcription begins only one cell diameter away from the niche cap cells. However, the mechanism to explain how such a steep gradient of response to BMP signaling is formed remains elusive.

In the study, the researchers developed a unique reagent and provided evidence that the differentiating daughter cell of GSCs, the cystoblasts (CBs), can develop resistance to BMP signaling through degradation of Tkv, the Drosophila BMP type I receptor. The research team then performed an immunoprecipitation experiment followed by mass spectrometry and found that Fused (Fu), a serine/threonine kinase which has been identified as a positive regulator in hedgehog signaling, physically interacts with Tkv. Moreover, they provided extensive genetic and biochemical evidence that Fu functions in concert with Smurf, an E3 ligase, to terminate BMP signaling by regulating ubiquitination and proteolysis of Tkv in the CBs, thereby generating a steep gradient of BMP activity between GSCs and CBs. Finally, the researchers observed a conserved function for fu in antagonizing BMP/TGFβ signals inzebrafish embryonic development as well as in human cell cultures. These findings not only reveal a novel and conserved function of fu in controlling BMP/TGFβ signal-mediated developmental processes, but also provide a comprehensive view of mechanisms that produce both self-renewal and asymmetry in the division of stem cells. This work was published in the recent issue of Cell (http://www.cell.com/abstract/S0092-8674(10)01302-4).

The study was supported by grants from the National Basic Research Program of China, NSFC and CAS.