Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Brain development: Fate of brain progenitor cells hinges on getting the timing right

02.05.2014

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 number of proliferating neural progenitors (shown in red) is significantly decreased in the brains of Trrap-deficient mice (BOTTOM) compared to the brains of control mice (TOP).

Courtesy of Dr. Alicia Tapias, Leibniz-Institute for Age Research – Fritz Lipmann Institute (FLI), Jena, Germany

“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

Contact:
Gina Kirchweger
Leibniz Institute for Age Research – Fritz Lipmann Institute (FLI)
Beutenbergstraße 11, 07745 Jena
Phone: +49 (0) 3641 656373
Cell: +49 (0) 151 58229052
Email: gkirchweger@fli-leibniz.de

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

Weitere Informationen:

http://www.fli-leibniz.de - Homepage Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI)

Dr. Kerstin Wagner | idw - Informationsdienst Wissenschaft

Further reports about: Brain Cell DNA FLI Leibniz-Institut epigenetic fate genes neurons progenitor self-renewal

More articles from Life Sciences:

nachricht Scientists spin artificial silk from whey protein
24.01.2017 | Deutsches Elektronen-Synchrotron DESY

nachricht Choreographing the microRNA-target dance
24.01.2017 | UT Southwestern Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Scientists spin artificial silk from whey protein

X-ray study throws light on key process for production

A Swedish-German team of researchers has cleared up a key process for the artificial production of silk. With the help of the intense X-rays from DESY's...

Im Focus: Quantum optical sensor for the first time tested in space – with a laser system from Berlin

For the first time ever, a cloud of ultra-cold atoms has been successfully created in space on board of a sounding rocket. The MAIUS mission demonstrates that quantum optical sensors can be operated even in harsh environments like space – a prerequi-site for finding answers to the most challenging questions of fundamental physics and an important innovation driver for everyday applications.

According to Albert Einstein's Equivalence Principle, all bodies are accelerated at the same rate by the Earth's gravity, regardless of their properties. This...

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Breaking the optical bandwidth record of stable pulsed lasers

24.01.2017 | Physics and Astronomy

Choreographing the microRNA-target dance

24.01.2017 | Life Sciences

Spanish scientists create a 3-D bioprinter to print human skin

24.01.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>