Just like musicians in a philharmonic orchestra look to the conductor for their cues, stem cells in charge of generating the dazzling number and variety of cells that build the developing brain rely on molecular signals to get the timing right. Now, scientists at the Leibniz Institute for Age Research add a new and unexpected mechanism to the list of cues that ensure that neural stem cells keep the beat. Their findings, published in the May 1, 2014, edition of the journal Cell Stem Cell, lay the groundwork for new approaches to stimulate the self-renewal and regenerative capacity of adult brain stem cells to treat neurodegeneration and other brain injuries.
During embryonic brain development, neural stem cells pass through a series of tightly regulated stages: from omnipotent stem cell to specialized progenitor capable of producing only certain types of neurons or support cells. If the timing of any of these transitions is just slightly off, it will result in substantial changes in the total number of neurons and ultimately overall brain size.
“The correct timing of fate decisions by neuronal stem cells is fundamental for building the necessary fine brain architecture,” explains Zhao-Qi Wang, Ph.D., the study’s senior author.
Wang and this team discovered that Trrap, a protein better known for its general role in facilitating the gene expression machinery’s access to DNA, prevents actively dividing neural progenitors from dawdling. Without Trrap, dividing cells slow down—loosing their ability for self-renewal and differentiating into neurons prematurely.
“By maintaining the balance between self-renewal and differentiation of neural progenitors, Trrap ensures the availability of enough neuron-producing progenitors to build a healthy brain,” says Wang.
When genes are turned on to serve as templates for proteins, the tightly wound DNA must unfurl just enough to allow the machinery that reads the encoded genetic information to slip in. Their access is mainly regulated through enzymes that add small chemical flags to the histone spools that keep the DNA inside a cell’s nucleus neatly organized. One of the best-studied modifications is the addition of acetyl groups, which is catalyzed by an enzyme known as histone acetyltransferase or HAT, for short. Trrap is its well-known and indispensible helpmate.
These histone modifications—often referred to as epigenetic changes—play an important role in creating distinct patterns of gene expression essential for self-renewal and differentiation of stem cells but the details are still somewhat unclear. “We still know very little about the specific molecular mechanisms that link epigenetic patterns to the fate of stem cells,” explains postdoctoral researcher and lead author Alicia Tapias, Ph.D.
To learn more, she generated mice that lacked Trrap only in the central nervous system. A first exam of the newborn mice revealed severe developmental defects in the brain. Their brains were about 40 percent smaller, with fewer dividing cells and increased cell death in the cortex—the largest brain structure and seat of higher cognitive functions.
When she followed the fate of neuronal progenitors during embryonic development, it quickly became clear that a highly proliferative subpopulation of neural progenitors known as apical progenitors, prematurely differentiated into basal progenitors, which are capable of generating neurons but, at least in mice, are unable to proliferate.
A genome-wide analysis of gene expression of Trrap-deficient cells brought the research team a step closer to pinpointing the reasons behind the apical progenitors’ change of fate: Deleting Trrap specifically lowered the expression of cell cycle genes, most prominently those governed by E2F, a family of well known cell cycle regulators.
“When we measured cell cycle length in apical progenitors lacking Trrap it was twice as long as in normal control cells, while cycle length in basic progenitors was only slightly delayed,” says Tapias. Overexpression of cell cycle activators Cyclin A2 and Cyclin B1 in Trrap-deficient neural progenitors brought them back up to speed and prevented those cells from differentiating prematurely.
“Our experiments highlight that HAT regulates a specific group of cell cycle genes,” explains Wang and adds that, “this information may shed light on understanding of the epigenetic modulation in neurological behavior and cell fate of adult stem cells in our brains.”
+++ NOT FOR PUBLIC RELEASE BEFORE May 1, 2014 at 12 p.m. EST +++
Tapias A, Zhou ZW, Shi Y, Chong Z, Wang P, Groth M, Platzer M, Huttner W, Herceg Z, Yang YG, Wang ZQ. Trrap-dependent histone acetylation specifically regulates cell cycle gene transcription to control neural progenitor fate decisions. Cell Stem Cell (2014). Doi: dx.doi.org/10.1016/j.stem.2014.04.001; http://www.cell.com/cell-stem-cell/home
Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI)
Beutenbergstraße 11, 07745 Jena
Phone: +49 (0) 3641 656373
Cell: +49 (0) 151 58229052
About the FLI:
The Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI) is the first German research organization dedicated to biomedical aging research since 2004. More than 330 members from over 30 nations explore the molecular mechanisms underlying aging processes and age-associated diseases. For more information, please visit: http://www.fli-leibniz.de
About the Leibniz Association
The Leibniz Association connects 89 independent research institutions that range in focus from the natural, engineering and environmental sciences via economics, spatial and social sciences to the humanities. Leibniz institutes address issues of social, economic and ecological relevance. They conduct knowledge-driven and applied basic research, maintain scientific infrastructure and provide research-based services.
The Leibniz Association identifies focus areas for knowledge transfer to policy-makers, academia, business and the public. Leibniz institutions collaborate intensively with universities – in the form of “WissenschaftsCampi” (thematic partnerships between university and non-university research institutes), for example – as well as with industry and other partners at home and abroad. They are subject to an independent evaluation procedure that is unparalleled in its transparency. Due to the importance of the institutions for the country as a whole, they are funded jointly by the Federation and the Länder, employing some 17,200 individuals, including 8,200 researchers. The entire budget of all the institutes is approximately 1.5 billion EUR. For more information, please visit http://www.leibniz-gemeinschaft.de/en
http://www.fli-leibniz.de - Homepage Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI)
Dr. Kerstin Wagner | idw - Informationsdienst Wissenschaft
New mechanisms uncovered explaining frost tolerance in plants
26.09.2016 | Technische Universität München
Chains of nanogold – forged with atomic precision
23.09.2016 | Suomen Akatemia (Academy of Finland)
The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.
“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...
With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.
Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...
For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.
Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...
At AKL’16, the International Laser Technology Congress held in May this year, interest in the topic of process control was greater than expected. Appropriately, the event was also used to launch the Industry Working Group for Process Control in Laser Material Processing. The group provides a forum for representatives from industry and research to initiate pre-competitive projects and discuss issues such as standards, potential cost savings and feasibility.
In the age of industry 4.0, laser technology is firmly established within manufacturing. A wide variety of laser techniques – from USP ablation and additive...
Every three years, the plastics industry gathers at K, the international trade fair for plastics and rubber in Düsseldorf. The Fraunhofer Institute for Laser Technology ILT will also be attending again and presenting many innovative technologies, such as for joining plastics and metals using ultrashort pulse lasers. From October 19 to 26, you can find the Fraunhofer ILT at the joint Fraunhofer booth SC01 in Hall 7.
K is the world’s largest trade fair for the plastics and rubber industry. As in previous years, the organizers are expecting 3,000 exhibitors and more than...
23.09.2016 | Event News
20.09.2016 | Event News
16.09.2016 | Event News
26.09.2016 | Materials Sciences
26.09.2016 | Materials Sciences
26.09.2016 | Materials Sciences