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 How molecules teeter in a laser field
18.01.2019 | Forschungsverbund Berlin

nachricht Discovery of enhanced bone growth could lead to new treatments for osteoporosis
18.01.2019 | University of California - Los Angeles

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Ten-year anniversary of the Neumayer Station III

The scientific and political community alike stress the importance of German Antarctic research

Joint Press Release from the BMBF and AWI

The Antarctic is a frigid continent south of the Antarctic Circle, where researchers are the only inhabitants. Despite the hostile conditions, here the Alfred...

Im Focus: Ultra ultrasound to transform new tech

World first experiments on sensor that may revolutionise everything from medical devices to unmanned vehicles

The new sensor - capable of detecting vibrations of living cells - may revolutionise everything from medical devices to unmanned vehicles.

Im Focus: Flying Optical Cats for Quantum Communication

Dead and alive at the same time? Researchers at the Max Planck Institute of Quantum Optics have implemented Erwin Schrödinger’s paradoxical gedanken experiment employing an entangled atom-light state.

In 1935 Erwin Schrödinger formulated a thought experiment designed to capture the paradoxical nature of quantum physics. The crucial element of this gedanken...

Im Focus: Nanocellulose for novel implants: Ears from the 3D-printer

Cellulose obtained from wood has amazing material properties. Empa researchers are now equipping the biodegradable material with additional functionalities to produce implants for cartilage diseases using 3D printing.

It all starts with an ear. Empa researcher Michael Hausmann removes the object shaped like a human ear from the 3D printer and explains:

Im Focus: Elucidating the Atomic Mechanism of Superlubricity

The phenomenon of so-called superlubricity is known, but so far the explanation at the atomic level has been missing: for example, how does extremely low friction occur in bearings? Researchers from the Fraunhofer Institutes IWM and IWS jointly deciphered a universal mechanism of superlubricity for certain diamond-like carbon layers in combination with organic lubricants. Based on this knowledge, it is now possible to formulate design rules for supra lubricating layer-lubricant combinations. The results are presented in an article in Nature Communications, volume 10.

One of the most important prerequisites for sustainable and environmentally friendly mobility is minimizing friction. Research and industry have been dedicated...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Our digital society in 2040

16.01.2019 | Event News

11th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Aachen, 3-4 April 2019

14.01.2019 | Event News

ICTM Conference 2019: Digitization emerges as an engineering trend for turbomachinery construction

12.12.2018 | Event News

 
Latest News

Additive manufacturing reflects fundamental metallurgical principles to create materials

18.01.2019 | Materials Sciences

How molecules teeter in a laser field

18.01.2019 | Life Sciences

The cytoskeleton of neurons has been found to be involved in Alzheimer's disease

18.01.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>