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
Single atom alloy platinum-copper catalysts cut costs, boost green technology
09.10.2015 | Tufts University
Controllable protein gates deliver on-demand permeability in artificial nanovesicles
09.10.2015 | Universität Basel
Nondestructive material testing (NDT) is a fast and effective way to analyze the quality of a product during the manufacturing process. Because defective materials can lead to malfunctioning finished products, NDT is an essential quality assurance measure, especially in the manufacture of safety-critical components such as automotive B-pillars. NDT examines the quality without damaging the component or modifying the surface of the material. At this year's Blechexpo trade fair in Stuttgart, Fraunhofer IZFP will have an exhibit that demonstrates the nondestructive testing of high-strength automotive body parts using 3MA. The measurement results are available in a matter of seconds.
To minimize vehicle weight and fuel consumption while providing the highest level of crash safety, automotive bodies are reinforced with elements made from...
The MICADO camera, a first light instrument for the European Extremely Large Telescope (E-ELT), has entered a new phase in the project: by agreeing to a Memorandum of Understanding, the partners in Germany, France, the Netherlands, Austria, and Italy, have all confirmed their participation. Following this milestone, the project's transition into its preliminary design phase was approved at a kick-off meeting held in Vienna. Two weeks earlier, on September 18, the consortium and the European Southern Observatory (ESO), which is building the telescope, have signed the corresponding collaboration agreement.
As the first dedicated camera for the E-ELT, MICADO will equip the giant telescope with a capability for diffraction-limited imaging at near-infrared...
Self-driving cars will be on our streets in the foreseeable future. In Graz, research is currently dedicated to an innovative driver assistance system that takes over control if there is a danger of collision. It was nature that inspired Dr Manfred Hartbauer from the Institute of Zoology at the University of Graz: in dangerous traffic situations, migratory locusts react around ten times faster than humans. Working together with an interdisciplinary team, Hartbauer is investigating an affordable collision detector that is equipped with artificial locust eyes and can recognise potential crashes in time, during both day and night.
Inspired by insects
An interdisciplinary team of researchers has built the first prototype of a miniature particle accelerator that uses terahertz radiation instead of radio...
At present, tiny magnetic whirls – so called skyrmions – are discussed as promising candidates for bits in future robust and compact data storage devices. At...
01.10.2015 | Event News
30.09.2015 | Event News
17.09.2015 | Event News
09.10.2015 | Earth Sciences
09.10.2015 | Life Sciences
09.10.2015 | Life Sciences