Nav: Home

Neurobiology: Doubly secured

May 20, 2019

Ludwig-Maximilians-Universitaet (LMU) in Munich researchers have used CRISPR technology to probe the mechanisms that guide the developmental trajectories of stem cells in the brain. The results show that crucial cellular switches are doubly protected against unintended activation.

Higher eukaryotic organisms are made up of a wide variety of specialized cell types. The precise identity and function of each individual cell is established by molecular processes that control gene expression during the course of its development. Proteins known as master transcription factors play a vital role in this context. They are the key switching elements that initiate the specific genetic programs which determine cell identity. The genes that code for these proteins must therefore be tightly controlled, as their improper activation could endanger the integrity of the entire organism by effectively overriding the previously established cell state. Researchers led by Dr. Stefan Stricker of the Munich Center for Neurosciences in LMU's Biomedical Center and the Helmholtz Zentrum München have now shown that the progenitors of nerve cells use a double-lock mechanism to avoid untimely production of master transcription factors. The study appears in the online journal Nature Communications.

The project actually set out to address a different question. "We initially wanted to investigate how genes can be turned on and off with the help of the CRISPR-Cas9 technique," Stricker says. In order to test technical aspects of the methodology in a system that is directly relevant for the differentiation of cell types, he and his colleagues chose the mouse Sox1 gene as their target. This gene codes for a master transcription factor that is known to be active in neural stem cells (NSCs). In all other classes of neural cells, including the somewhat more mature neuronal progenitor cells (NPCs), Sox1 is repressed. In the absence of the Sox1 protein, NSCs progressively lose the capacity to differentiate into neurons that transmit electrical signals.

Using the CRISPR/Cas9 approach, the researchers guided a trans-activating protein specifically to the Sox1 gene in NPCs in which the gene is normally inactive. Many other genes have already been shown to be activated by this method, but Sox1 responded very poorly. This finding suggested that reactivation of Sox1 in NPCs might be prevented by some special mechanism. To test this hypothesis, the LMU team then focused on the methylation pattern around the Sox1 gene in NPCs. Methylation - the addition of methyl (CH3) groups to certain nucleotide bases in the genomic DNA - can play a significant role in the epigenetic inactivation of genes. "To explore the role of methylation, we again made use of CRISPR-Cas9, this time to remove methyl groups from the DNA around the Sox1 gene," Stricker explains. "And indeed, the combination of targeted demethylation and transactivation allowed us to reactivate Sox1. This is essentially equivalent to the rejuvenating the cells, as revealed by the fact that they recovered their stem-cell properties and were able to differentiate into neurons."

The authors of the new study believe that, in addition to inhibiting expression , cells impose a specific repressive chromatin layer on genes that control cell identity, which protects them from inadvertent activation. Together, these measures act as a double lock to prevent reactivation of such genes after they have done their job. Nevertheless, the ability to reactivate repressed genes might also make it possible to cause neuronal progenitor cells revert to the stem-cell state. Such rejuvenated stem cells would have great therapeutic potential. "But the route from our basic research to the application of reactivated stem cells is a very long one," Stricker cautions.

Ludwig-Maximilians-Universität München

Related Stem Cells Articles:

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.
First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.
Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.
The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.
Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.
New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.
NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.
Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.
In mice, stem cells seem to work in fighting obesity! What about stem cells in humans?
This release aims to summarize the available literature in regard to the effect of Mesenchymal Stem Cells transplantation on obesity and related comorbidities from the animal model.
TSRI researchers identify gene responsible for mesenchymal stem cells' stem-ness'
Researchers at The Scripps Research Institute recently published a study in the journal Cell Death and Differentiation identifying factors crucial to mesenchymal stem cell differentiation, providing insight into how these cells should be studied for clinical purposes.
More Stem Cells News and Stem Cells Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

There's so much we've yet to explore–from outer space to the deep ocean to our own brains. This hour, Manoush goes on a journey through those uncharted places, led by TED Science Curator David Biello.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Dispatch 2: Every Day is Ignaz Semmelweis Day
It began with a tweet: "EVERY DAY IS IGNAZ SEMMELWEIS DAY." Carl Zimmer – tweet author, acclaimed science writer and friend of the show – tells the story of a mysterious, deadly illness that struck 19th century Vienna, and the ill-fated hero who uncovered its cure ... and gave us our best weapon (so far) against the current global pandemic. This episode was reported and produced with help from Bethel Habte and Latif Nasser. Support Radiolab today at