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 Correct antibiotic dosing could preserve lung microbial diversity in cystic fibrosis
22.02.2019 | Children's National Health System

nachricht Researchers find trigger that turns strep infections into flesh-eating disease
19.02.2019 | Houston Methodist

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: (Re)solving the jet/cocoon riddle of a gravitational wave event

An international research team including astronomers from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has combined radio telescopes from five continents to prove the existence of a narrow stream of material, a so-called jet, emerging from the only gravitational wave event involving two neutron stars observed so far. With its high sensitivity and excellent performance, the 100-m radio telescope in Effelsberg played an important role in the observations.

In August 2017, two neutron stars were observed colliding, producing gravitational waves that were detected by the American LIGO and European Virgo detectors....

Im Focus: Light from a roll – hybrid OLED creates innovative and functional luminous surfaces

Up to now, OLEDs have been used exclusively as a novel lighting technology for use in luminaires and lamps. However, flexible organic technology can offer much more: as an active lighting surface, it can be combined with a wide variety of materials, not just to modify but to revolutionize the functionality and design of countless existing products. To exemplify this, the Fraunhofer FEP together with the company EMDE development of light GmbH will be presenting hybrid flexible OLEDs integrated into textile designs within the EU-funded project PI-SCALE for the first time at LOPEC (March 19-21, 2019 in Munich, Germany) as examples of some of the many possible applications.

The Fraunhofer FEP, a provider of research and development services in the field of organic electronics, has long been involved in the development of...

Im Focus: Regensburg physicists watch electron transfer in a single molecule

For the first time, an international team of scientists based in Regensburg, Germany, has recorded the orbitals of single molecules in different charge states in a novel type of microscopy. The research findings are published under the title “Mapping orbital changes upon electron transfer with tunneling microscopy on insulators” in the prestigious journal “Nature”.

The building blocks of matter surrounding us are atoms and molecules. The properties of that matter, however, are often not set by these building blocks...

Im Focus: University of Konstanz gains new insights into the recent development of the human immune system

Scientists at the University of Konstanz identify fierce competition between the human immune system and bacterial pathogens

Cell biologists from the University of Konstanz shed light on a recent evolutionary process in the human immune system and publish their findings in the...

Im Focus: Transformation through Light

Laser physicists have taken snapshots of carbon molecules C₆₀ showing how they transform in intense infrared light

When carbon molecules C₆₀ are exposed to an intense infrared light, they change their ball-like structure to a more elongated version. This has now been...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Global Legal Hackathon at HAW Hamburg

11.02.2019 | Event News

The world of quantum chemistry meets in Heidelberg

30.01.2019 | Event News

Our digital society in 2040

16.01.2019 | Event News

 
Latest News

JILA researchers make coldest quantum gas of molecules

22.02.2019 | Physics and Astronomy

Understanding high efficiency of deep ultraviolet LEDs

22.02.2019 | Materials Sciences

Russian scientists show changes in the erythrocyte nanostructure under stress

22.02.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>