Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecule found to be critical for kidney development

09.09.2003


By taking advantage of techniques developed in the search for Alzheimer’s treatments, a team of researchers has discovered that a molecule called Notch is essential for the development of critical kidney cells. The study, published online and in the Oct. 15 issue of the journal Development, provides key information about kidney development that could have implications for tissue regeneration.



"Tissue transplantation is fantastic but it would be so much better if we could instead raise organs from a patient’s own cells," says lead investigator Raphael Kopan, Ph.D., associate professor of medicine and of molecular biology and pharmacology at Washington University School of Medicine in St. Louis. "Before we can actually trick cells into doing what we want them to do we really need to understand every detail about how the organ is put together."

Using an antibody that specifically identifies the active form of Notch, Kopan’s group observed that the protein is extremely active in the kidney at an earlier stage than previously thought. So they teamed up with kidney development expert Jeffrey H. Miner, Ph.D., associate professor of medicine and of cell biology and physiology, to investigate further. First, though, they had to resolve a methodological conundrum: How do you study the effect of Notch in the kidney if animals without Notch die before the kidney begins to form?


The answer came from an entirely different field: Alzheimer’s disease. In 2001, Kopan’s team discovered that a group of potential Alzheimer’s drugs that inhibit a protein complex called gamma-secretase also interfere with Notch. For clinical purposes, the drugs have since been refined to minimize their potentially dangerous effects on Notch. But drugs that severely inhibit this protein are perfect for studying its activity in laboratory animals.

"We took advantage of developments in different fields to allow us to do this analysis," says Kopan. "Without collaborating and combining our knowledge, we would not have been able to conduct this study."

The team removed both kidneys from normal mice during early development and placed them in organ culture. They treated one kidney from each mouse with a gamma-secretase inhibitor and showed that this process prevented all Notch signaling. The second kidney from each animal was used for comparison.

After three days of treatment with the inhibitor there were fewer and less developed tubular structures in the treated compared to the untreated kidneys. These differences became more pronounced after five days of treatment: Tubes in untreated tissue branched an average of 10 times and the tips of these branches had consistent, small diameters; tubes in treated tissue only branched a maximum of eight times and their branches were more irregularly shaped.

For the most part, the treated cells successfully passed through the first stage of development, in which they evolved from embryonic, precursor cells into epithelial cells, which form the lining of the organ. But the most pronounced abnormalities occurred in the next stage of development, in which the cells become more specialized.

Urine is formed in the kidney’s functional units, called nephrons. Within each nephron are several structures, including a long, winding tube called the proximal tubule and octopus-shaped cells called podocytes that wrap their "feet" around blood vessels. After two days of treatment with the gamma-secretase inhibitor, neither podocytes nor proximal tubule cells formed. Another nephron structure, the distal tubule, was not disturbed.

"The most exciting finding was that Notch signaling appears to tell some cells to become podocytes from a mass of non-specialized epithelial cells," Miner says. "This shows that Notch is involved at an earlier stage of podocyte development than any other factor that’s been identified so far."

Even more surprising was that the tissue lost the ability to form podocytes after a certain amount of time. If Notch signaling resumed after two days, podocytes recovered. But if it did not resume until three days or more, the cells instead developed into those that comprise the proximal tubule.

"It’s as if the cell can tell time," Kopan explains. "After three or four days without Notch signaling, it realizes it will never become a podocyte and decides to respond to the next signal it receives."

Next, the team hopes to further differentiate the role of Notch in formation of each component of the nephron, and to determine the specific genes responsible for this particular developmental pathway.


Cheng HT, Miner JH, Lin MH, Tansey MG, Roth K, Kopan R. g-Secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podoctye and proximal tubule formation in developing mouse kidney. Development, vol. 130, pp. 5031-5042, Oct. 15, 2003.

Funding from the National Institutes of Health, the Alzheimer’s Association, the Zenith award, the American Heart Association and the March of Dimes supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Gila Z. Reckess | EurekAlert!
Further information:
http://medinfo.wustl.edu/

More articles from Life Sciences:

nachricht Unique genome architectures after fertilisation in single-cell embryos
30.03.2017 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

nachricht Transport of molecular motors into cilia
28.03.2017 | Aarhus University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

'On-off switch' brings researchers a step closer to potential HIV vaccine

30.03.2017 | Health and Medicine

Penn studies find promise for innovations in liquid biopsies

30.03.2017 | Health and Medicine

An LED-based device for imaging radiation induced skin damage

30.03.2017 | Medical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>