Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Stem-cell defect underlies common genetic disorder

15.08.2003


Howard Hughes Medical Institute researchers have found that Hirschsprung disease, one of the most common genetic disorders, is caused by a defect that blocks neural stem cells from forming nerves that control the lower intestine.



Hirschsprung disease occurs in one in 5,000 live births and causes a potentially fatal disorder that prevents the proper transport of food through the gut. The new findings suggest that it might one day be possible to correct the disease by transplanting neural stem cells from a different part of the gut.

Neural crest stem cells (NCSCs) are cells that mature into neurons and supporting neural cells found in the gut. The studies provide important general insight into how stem cells -- the immature cells that can develop into mature nerve and other cells -- are controlled. While the properties of stem cells have been widely studied, relatively little is known about how they are regulated during development.


The researchers, led by Howard Hughes Medical Institute (HHMI) investigator Sean J. Morrison, HHMI associate Toshihide Iwashita, and graduate student Eve Kruger at the University of Michigan, published their findings in the August 15, 2003, issue of Science.

"Some of the genetic mutations that cause Hirschsprung have been identified, but they explain only about half the cases," said Morrison. "Our work identifies new genes whose mutations might underlie the disease. We’ve found the mechanism by which one type of mutation impairs the function of the neural crest stem cells that give rise to the enteric nervous system."

The researchers began by conducting a global comparison of genes expressed in whole mouse fetuses with those genes expressed only in the fetal gut NCSCs. To make this comparison, they applied RNA extracts from the two sources to microarrays, or "gene chips," which are arrays of thousands of gene probes that can signal the activity of specific genes. Using this process, the researchers found that the ten genes that were most highly expressed in the gut NCSCs relative to the whole fetus, included four that had already been linked to Hirschsprung disease in humans.

"This finding was exciting because if four of our top ten genes have already been implicated in Hirschsprung disease, it’s an attractive hypothesis that some of the other genes we found upregulated could also cause the disorder when mutated," said Morrison.

Subsequent studies by Morrison and his colleagues focused on understanding the function of one of the identified genes, called Ret. They chose Ret because it is known to code for a receptor protein that enables stem cells to respond to a neuronal guidance protein called GDNF (glial-derived neurotrophic factor). Mutations in either Ret or GDNF genes had already been shown to cause Hirschsprung disease in both humans and mice, said Morrison.

Using antibody markers and NCSC cultures, the researchers confirmed that Ret proteins were expressed on the surface of stem cells and that the Ret receptor was required for the migration of the stem cells in response to GDNF in culture.

To test whether the loss of Ret prevented normal NCSC migration in the gut, the researchers examined the behavior of the NCSCs in the guts of Ret-deficient mice. These experiments revealed a dramatic decrease in the migration of NCSCs in the animals’ guts.

"Until this work, what was missing was whether these molecular pathways act within neural crest stem cells to promote migration," said Morrison. "Our finding that these pathways are all expressed in neural crest stem cells and that they regulate the function of the cells, provides a cellular locus for people to study directly how those pathways interact."

Morrison also speculated that the research could have implications for correcting the genetic defect underlying Hirschsprung disease. "Our findings suggest that in people with mutations in Ret, the primary reason the enteric nervous system doesn’t form in the hindgut is because neural crest stem cells just never migrate into the hindgut. Perhaps we can bypass that migratory defect by taking stem cells from the foregut, expanding them in culture, and then transplanting them into the hindgut."

Morrison emphasized that the findings demonstrate the value of a relatively new approach that uses microarrays for identifying activated genes and then knocking out those activated genes in mice to determine how those genes regulate stem cell function. "We think that this represents a powerful combination for getting important insights into the causes of other types of birth defects or other types of diseases," he said.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org/

More articles from Health and Medicine:

nachricht New malaria analysis method reveals disease severity in minutes
14.08.2017 | University of British Columbia

nachricht New type of blood cells work as indicators of autoimmunity
14.08.2017 | Instituto de Medicina Molecular

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>