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From fruit flies to humans, adult stem cells either self-renew through cell division or differentiate to replace worn-out or damaged organs and tissues.
Understanding the molecular mechanisms controlling this balance is needed to develop regenerative disease therapies for injured or aged tissue.
In the current issue of the journal Nature, scientists at the Stowers Institute for Medical Research report that competition between two proteins, Bam and COP9, balances the self-renewal and differentiation functions of ovarian germline stem cells (GSCs) in fruit flies (Drosophila melanogaster).
"Bam is the master differentiation factor in the Drosophila female Germ Stem Cell (GSC) system," says Stowers Investigator Ting Xie, Ph.D., and senior author of the Nature paper. "In order to carry out the switch from self-renewal to differentiation, Bam must inactivate self-renewing factors as well as activate the functions of differentiation factors."
Bam, which is encoded by a gene with the unusual name of bag-of-marbles, is produced at high levels in differentiating cells and very low levels in Germ Stem Cells or GSCs of fruit flies.
Among the self-renewing factors targeted by Bam is the COP9 signalosome (CSN), a multi-functional complex that contains eight protein sub-units (CSN1 to CSN8). Xie and collaborators discovered that Bam and the COP9 sub-unit known as CSN4 have opposite functions in regulating the fate of GSCs in female fruit flies.
Bam can switch COP9 function from self-renewal to differentiation by sequestering and antagonizing CSN4.
"Bam directly binds to CSN4, preventing its association with the seven other COP9 components via protein competition," he adds. CSN4 is the only COP9 sub-unit that can interact with Bam.
In the Nature paper, Xie's lab reports that CSN4 is the only one of the eight sub-units that is not involved in the regulation of GSC differentiation of female fruit flies.
"One possible explanation for the opposite effects of CSN4 and the other CSN proteins is that by sequestering CSN4, Bam allows the other CSN proteins to promote differentiation functions."
Ting Xie, Ph.D., lab director and senior author, Nature paper.
Xie's lab also has shown that Bam inactivates the function of another promoter of GSC self-renewal, the eukaryotic initiation factor-4A (eIF4A), which plays a role in gene expression. Xie points out that other labs have also revealed Bam suppresses the expression of the protein Nanos. Like COP9, Nanos is regarded as essential to establishing and maintaining self-renewing Germ Stem Cells in female fruit flies.
The balance between stem cell self-renewal and differentiation is controlled by intrinsic factors and niche signals1, 2. In the Drosophila melanogaster ovary, some intrinsic factors promote germline stem cell (GSC) self-renewal, whereas others stimulate differentiation3. However, it remains poorly understood how the balance between self-renewal and differentiation is controlled. Here we use D. melanogaster ovarian GSCs to demonstrate that the differentiation factor Bam controls the functional switch of the COP9 complex from self-renewal to differentiation via protein competition. The COP9 complex is composed of eight Csn subunits, Csn1–8, and removes Nedd8 modifications from target proteins4, 5. Genetic results indicated that the COP9 complex is required intrinsically for GSC self-renewal, whereas other Csn proteins, with the exception of Csn4, were also required for GSC progeny differentiation. Bam-mediated Csn4 sequestration from the COP9 complex via protein competition inactivated the self-renewing function of COP9 and allowed other Csn proteins to promote GSC differentiation. Therefore, this study reveals a protein-competition-based mechanism for controlling the balance between stem cell self-renewal and differentiation. Because numerous self-renewal factors are ubiquitously expressed throughout the stem cell lineage in various systems, protein competition may function as an important mechanism for controlling the self-renewal-to-differentiation switch.
In addition to Xie, other members of the Stowers team were first co-authors Lei Pan, Ph.D., and Su Wang, Ph.D., Changjiang Weng, Ph.D., Xiaoqing Song, and Junjing Yu. Also contributing were Jin Sun, Ph.D., Tinglin Lu, Zhi-Hao Yang, and Jianquan Ni, Tsinghua University, Beijing, China; Hong Tang, Ph.D., Chinese Academy of Sciences, Beijing; Joseph K. Park, M.D., Ph.D., and Dennis M. McKearin, Ph.D., University of Texas Southwestern Medical Center, Dallas, Texas; and Daniel A. Chamovitz, Ph.D., Tel Aviv University, Tel Aviv, Israel.
The Stowers Institute for Medical Research, National Natural Science Foundation of China (31370909) Ministry of Science and Technology of China (2012CB518900) and the National Institutes of Health (R01DC008003) funded the research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
About the Stowers Institute for Medical Research
The Stowers Institute for Medical Research is a non-profit, basic biomedical research organization dedicated to improving human health by studying the fundamental processes of life. Jim Stowers, founder of American Century Investments, and his wife, Virginia, opened the Institute in 2000. Since then, the Institute has spent over one billion dollars in pursuit of its mission.
Currently, the Institute is home to nearly 550 researchers and support personnel; over 20 independent research programs; and more than a dozen technology-development and core facilities.