Adult organisms ranging from fruit flies to humans harbor adult stem cells, some of which renew themselves through cell division while others differentiate into the specialized cells needed to replace worn-out or damaged organs and tissues.
Courtesy: Ting Xie, Ph.D., Stowers Institute for Medical Research
A bam mutant fruit fly ovary, known as the germanium, contains only adult stem cell-like cells (red) and spherical spectrosome (green). The accumulation of only adult stem cell-like cells indicates a mutation in the master differentiation factor bam completely blocks germline stem cell lineage differentiation.
Understanding the molecular mechanisms that control the balance between self-renewal and differentiation in adult stem cells is an important foundation for developing therapies to regenerate diseased, 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 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 the functions of self-renewing factors as well as activate the functions of differentiation factors.”
Bam, which is encoded by the gene with the unusual name of bag-of-marbles, is expressed at high levels in differentiating cells and very low levels in GSCs of fruit flies.
Among the self-renewing factors targeted by Bam is the COP9 signalosome (CSN), an evolutionarily conserved, multi-functional complex that contains eight protein sub-units (CSN1 to CSN8). Xie and his 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, Xie says. “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.
“This study has offered a novel way for Bam to carry out the switch from self-renewal to differentiation,” says Xie, whose lab uses a combination of genetic, molecular, genomic and cell biological approaches to investigate GSCs as well as somatic stem cells of fruit flies.
In the Nature paper, Xie’s lab also 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 the sequestration of CSN4 by Bam allows the other CSN proteins to have differentiation-promoting functions,” he says.
“As a powerful model system for studying adult stem cells, Drosophila female GSCs have revealed many novel regulatory strategies which have been later confirmed to be generally true,” adds Su Wang, a co-first author of the paper and also a graduate student in Department of Anatomy and Cell Biology at University of Kansas Medical Center.
In their future studies, Xie says that he hopes to identify the molecular mechanisms that enable COP9 with CSN4 to promote GSC self-renewal and without CSN4 to enhance differentiation.
The findings reported in Nature build upon previous research in Xie’s lab to understand the molecular mechanisms that influence GSC self-renewal and differentiation. The lab previously found that Bam is required to repress the expression of E-cadherin, a cell-to-cell adhesion molecule that tethers adult stem cells to their tissue niches and promotes GSC self-renewal.
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 studies in other labs have revealed that Bam also suppresses the expression of the protein Nanos. Like COP9, Nanos is regarded as essential to establishing and maintaining self-renewing GSCs in female fruit flies.
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.
Kim Bland | newswise
Gene switch may repair DNA and prevent cancer
12.02.2016 | Institute for Integrated Cell-Material Sciences at Kyoto University
New method opens crystal clear views of biomolecules
11.02.2016 | Deutsches Elektronen-Synchrotron DESY
Today, plants and microorganisms are heavily used for the production of medicinal products. The production of biopharmaceuticals in plants, also referred to as “Molecular Pharming”, represents a continuously growing field of plant biotechnology. Preferred host organisms include yeast and crop plants, such as maize and potato – plants with high demands. With the help of a special algal strain, the research team of Prof. Ralph Bock at the Max Planck Institute of Molecular Plant Physiology in Potsdam strives to develop a more efficient and resource-saving system for the production of medicines and vaccines. They tested its practicality by synthesizing a component of a potential AIDS vaccine.
The use of plants and microorganisms to produce pharmaceuticals is nothing new. In 1982, bacteria were genetically modified to produce human insulin, a drug...
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...
The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.
Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...
Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.
The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).
Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels
A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...
12.02.2016 | Event News
09.02.2016 | Event News
02.02.2016 | Event News
12.02.2016 | Physics and Astronomy
12.02.2016 | Life Sciences
12.02.2016 | Medical Engineering