Featured Research

from universities, journals, and other organizations

Rett Syndrome gene dysfunction redefined

Date:
October 3, 2013
Source:
Whitehead Institute for Biomedical Research
Summary:
Researchers have discovered that the protein product of the gene MECP2, which is mutated in about 95% of Rett syndrome patients, is a global activator of neuronal gene expression. Mutations in the protein can cause decreased gene transcription, reduced protein synthesis, and severe defects in the AKT/mTOR signaling pathway.

Rett syndrome, an autism spectrum disorder caused most often by a mutation in the gene MECP2, affects one in 10,000 girls. To study the disease, researchers in the lab of Whitehead Founding Member Rudolf Jaenisch created MECP2-deficient neurons derived from human embryonic stem cells. These cells (bottomr row of image) reflect both reduced cell size (stained green) and nucleus size (stained blue) as seen in patients' neurons, compared with wild type neurons (top row).
Credit: Courtesy of Cell Press

Whitehead Institute researchers have redefined the function of a gene whose mutation causes Rett syndrome, a neurodevelopmental autism spectrum disorder. This new research offers an improved understanding of the defects found in the neurons of Rett syndrome patients and could lead to novel therapies for the disease.

"The action of the MECP2 protein is just the opposite of how it was held for the past 15 years," says Whitehead Founding Member Rudolf Jaenisch, who is also a professor of biology at MIT. "It was thought that this protein globally repressed the expression of methylated DNA. What this work shows is when you do the analysis in a way that takes cell size into account -- cell size is very different in Rett neurons compared to wild type -- then suddenly we can see that the protein acts like a global activator. We've defined the function of MECP2 in a totally different way."

Rett syndrome is an X-linked genetic disease affecting one in 10,000 newborn girls. Infants with the disease appear to develop normally for their first six to 18 months, at which point their movement and language skills begin to deteriorate. Loss of speech, reduced head size, breathing and heart rhythm irregularities, and autistic-like symptoms are common by age four. Some symptoms may be treated with prescription drugs, but no cure or disease-modifying therapy exists. Previous work by the Jaenisch lab has provided some hope for the families of Rett patients. In a mouse model lacking the MECP2 gene, which is mutated in approximately 95% of girls with Rett syndrome, mice injected with the protein IGF-1 had more regular breathing and heart rhythms than did untreated mice. In addition, the brains of treated mice had greater mass and more of the vital neuronal projections that are missing in Rett syndrome mice and human patients.

In the current research, Yun Li, a postdoctoral researcher in the Jaenisch lab, analyzed the global gene expression of MECP2-deficient neurons derived from human embryonic stem cells. Unlike earlier research, Li took into account the Rett neurons' smaller size when comparing their gene expression to neurons with intact MECP2. The Rett neurons had decreased mRNA transcription, reduced protein synthesis, and severe defects in the AKT/mTOR signaling pathway, which is activated by IGF-1. Li's work is published in the October 2nd issue of Cell Stem Cell.

"We have always found it strange that MECP2 mutant mice, which share many of the severe neurological problems as really sick kids with Rett syndrome, have very few transcriptional changes detectable on a microarray. That doesn't seem to support a global repressor role for the MECP2 protein. There had to be something wrong," says Li. "Now we have a much better understanding of the function of MECP2, and the severity of the disease on a cellular level. Knowing that human Rett neurons are impaired in both global transcription and translation is important for us to design therapeutic strategies for Rett. Growth factors such as BDNF and IGF-1 are known to activate the AKT/mTOR pathway and increase protein synthesis. Down the road, we are interested in further exploring the Akt/mTOR pathway, and investigate how activation of this pathway could reverse the disease."


Story Source:

The above story is based on materials provided by Whitehead Institute for Biomedical Research. The original article was written by Nicole Giese Rura. Note: Materials may be edited for content and length.


Journal Reference:

  1. Yun Li, Haoyi Wang, Julien Muffat, Albert W. Cheng, David A. Orlando, Jakob Lovén, Show-ming Kwok, Danielle A. Feldman, Helen S. Bateup, Qing Gao, Dirk Hockemeyer, Maisam Mitalipova, Caroline A. Lewis, Matthew G. Vander Heiden, Mriganka Sur, Richard A. Young, Rudolf Jaenisch. Global Transcriptional and Translational Repression in Human-Embryonic-Stem-Cell-Derived Rett Syndrome Neurons. Cell Stem Cell, 2013; 13 (4): 446 DOI: 10.1016/j.stem.2013.09.001

Cite This Page:

Whitehead Institute for Biomedical Research. "Rett Syndrome gene dysfunction redefined." ScienceDaily. ScienceDaily, 3 October 2013. <www.sciencedaily.com/releases/2013/10/131003121151.htm>.
Whitehead Institute for Biomedical Research. (2013, October 3). Rett Syndrome gene dysfunction redefined. ScienceDaily. Retrieved July 30, 2014 from www.sciencedaily.com/releases/2013/10/131003121151.htm
Whitehead Institute for Biomedical Research. "Rett Syndrome gene dysfunction redefined." ScienceDaily. www.sciencedaily.com/releases/2013/10/131003121151.htm (accessed July 30, 2014).

Share This




More Mind & Brain News

Wednesday, July 30, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

It's Not Just Facebook: OKCupid Experiments With Users Too

It's Not Just Facebook: OKCupid Experiments With Users Too

Newsy (July 29, 2014) — If you've been looking for love online, there's a chance somebody has been looking at how you're looking. Video provided by Newsy
Powered by NewsLook.com
How Your Face Can Leave A Good Or Bad First Impression

How Your Face Can Leave A Good Or Bad First Impression

Newsy (July 29, 2014) — Researchers have found certain facial features can make us seem more attractive or trustworthy. Video provided by Newsy
Powered by NewsLook.com
Losing Sleep Leaves You Vulnerable To 'False Memories'

Losing Sleep Leaves You Vulnerable To 'False Memories'

Newsy (July 27, 2014) — A new study shows sleep deprivation can make it harder for people to remember specific details of an event. Video provided by Newsy
Powered by NewsLook.com
University Quiz Implies Atheists Are Smarter Than Christians

University Quiz Implies Atheists Are Smarter Than Christians

Newsy (July 25, 2014) — An online quiz from a required course at Ohio State is making waves for suggesting atheists are inherently smarter than Christians. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins