Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study sheds light on signaling mechanism in stem cells, cancer

25.10.2005


UCSF scientists have illuminated a key step in a signaling pathway that helps orchestrate embryonic development. The finding, they say, could lead to insights into the development of stem cells, as well as birth defects and cancers, and thus fuel therapeutic strategies.

The study, reported in Nature (Oct. 13, 2005), focuses on the Hedgehog family of signaling molecules, which play a central role in directing development of the early embryo’s growth and spatial plan, as well as its later organ and limb development. Defects in Hedgehog signaling are a significant cause of some birth defects and cancers.

Secreted from one cell, a Hedgehog signal shoots to the surface receptor of a second cell, and then, in a rapid-fire succession of biochemical reactions, relays a message into the cell’s nucleus. There, it issues an instruction, prompting the cell to divide, or specialize into a particular cell type, or migrate to help form another part of the embryo, and so on. This transaction, known as signal transduction, is a ceaseless activity of embryonic development.



Scientists have long known that Hedgehog signaling requires the activity of a protein known as Smoothened. This has been demonstrated in animals ranging from insects to humans.

They have also known that defects in Smoothened, which only functions within Hedgehog signaling, are responsible for some cases of human cancers – most prominently a skin cancer known as basal cell carcinoma and a childhood brain cancer known as medulloblastoma -- as well as some birth defects.

However, they have not known how Smoothened executes its function, nor where it is located in the target cell.

Now, through a series of studies conducted in several types of cells in culture, and in zebrafish and mouse embryos, the UCSF scientists have answered both questions. In the process, they have revealed the critical role of a cellular component that until now has been a mystery: an antenna-like structure attached to cells known as the primary cilium.

The primary cilium, it turns out, serves as the fulcrum in a series of acrobatic like moves between the Hedgehog signal and the Smoothened protein. Once Hedgehog has latched on to its receptor on the target cell’s surface, it prompts the cell to move Smoothened, located in vesicles around the cell’s nucleus, to the primary cilium. The positioning of Smoothened on the cilium, in turn, prompts downstream signaling of Hedgehog signals into the nucleus, where the instructions are issued.

Just how or what the primary cilium is doing to promote Smoothened’s activity is not clear, say the researchers. However, its involvement in the process is a revelation.

Scientists elsewhere reported in Nature in (Nov. 6, 2003) that removal of the primary cilium from cells led to defects in neural patterning resulting from Hedgehog signaling. However, they didn’t know why.

"This study takes two mysteries – how Smoothened functions and the role of the primary cilium – and suggests a mechanism by which they are connected," says the senior author of the study, Jeremy Reiter, MD, PhD, a fellow in the UCSF Program in Developmental and Stem Cell Biology, which is part of the UCSF Institute for Stem Cell and Tissue Biology.

The implications for medical research, he says, are significant.

Hedgehog signals play an important role in prompting embryonic and adult stem cells to differentiate into some of the specialized cells that make up the body’s tissues -- such as those of the brain, pancreas and skin. The new finding, says Reiter, will advance scientists efforts to use signaling molecules to direct the differentiation of embryonic stem cells in the culture dish, with the goal of using them to replace or replenish damaged tissues in patients.

The discovery could be particularly important for neural stem cell research, says Arnold Kriegstein, MD, PhD, director of the UCSF Institute for Stem Cell and Tissue Biology. Kriegstein, a neural stem cell scientist, was not an author on the study.

"Hedgehog signaling plays a critical role in prompting the differentiation of neural stem cells into the various forms of neurons in the brain," he says. "The discovery of the importance of the cilium in Hedgehog signaling should significantly advance our understanding of the mechanisms involved," he says.

The finding should fuel research into the causes of certain birth defects (such as holoprosencephaly and limb defects) and cancers, says Reiter. Smoothened is already known to be a proto-oncogene, a normal gene that, if mutated, is capable of causing cancers. But its close involvement with the primary cilium suggests that the latter may also be implicated, suggesting a possible target for therapy.

More broadly, says Reiter, the primary cilium’s role in Hedgehog signaling indicates it is likely to function in other signaling pathways, as well.

The scientists moved in on the role of Smoothened and the primary cilium incrementally. First, driven by their interest in Smoothened, they set out to determine where it was expressed in the embryo. They did so by developing highly specific antibodies to the protein and applying them to the tissue of an eight-day mouse embryo. The study revealed that Smoothened was modestly upregulated in cells of the node, an important early organizer tissue within the mouse embryo, and was expressed predominantly along the primary cilium of these nodal cells. This was a significant surprise.

Second, to examine whether Smoothened’s movement from vesicles around the nucleus to the cilium was regulated by Hedgehog signals, they carried out two studies, one involving cultured epithelial and fibroblasts cells expressing Smoothened, another involving a mouse embryo. In both cases, one set of cells was exposed to Hedgehog signals. Another set was exposed to cyclopamine, a drug that blocks Smoothened’s function. In the cells exposed to the Hedgehog signals, Smoothened moved from the vesicles of the cell body to the cilium. In the cells exposed to cyclopamine, Smoothened was undetectable on the cilium.

Scientists have known that cyclopamine inhibits Hedgehog signaling and can prevent Hedgehog-dependent cancers from spreading. The demonstration that the drug affected Smoothened movement to the cilium suggests how cyclopamine inhibits the Hedgehog pathway, the researchers say, and shows that the correlation between Smoothened on the cilium and pathway activation is very tight.

Third, they examined whether the Smoothened protein included an amino acid sequence that other seven-transmembrane proteins require to move to the primary cilium and, if so, whether this sequence – a so-called "motif" – was essential to its relocation there. The answer to both questions was yes: A study of mouse cells in which Smoothened was mutated to lack the motif revealed that Smoothened no longer moved to the primary cilium.

Finally, to determine Smoothened’s function, they tested the mutant form of Smoothened that no longer could move to the primary cilium in epithelial cells in culture and in zebrafish embryos to see if the protein still functioned. It did not.

"Thus, not only does Smoothened ciliary localization depend up on Hedgehog signaling, but Hedgehog signaling depends on a Smoothened ciliary localization motif," says Reiter.

"Whether Smoothened functions at the cilium in all cell types remains to be determined. In addition, how Smoothened activates the Hedgehog pathway at the cilium remains unclear," he says. "But the current finding lays the groundwork for future studies that could ultimately have clinical benefit."

Co-authors of the study were Kevin C. Corbit, Pia Aanstad, Veena Singla, Andrew R. Norman and Didier Y.R. Stainier, PhD. All are members of the UCSF Program in Developmental and Stem Cell Biology and the UCSF Diabetes Center. Aanstad and Stainier are also members of the UCSF Department of Biochemistry and Biophysics. All are also members of the UCSF Institute for Stem Cell and Tissue Biology.

Jennifer O’Brien | EurekAlert!
Further information:
http://www.ucsf.edu

More articles from Studies and Analyses:

nachricht Multi-year study finds 'hotspots' of ammonia over world's major agricultural areas
17.03.2017 | University of Maryland

nachricht Diabetes Drug May Improve Bone Fat-induced Defects of Fracture Healing
17.03.2017 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke

All articles from Studies and Analyses >>>

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

Researchers shoot for success with simulations of laser pulse-material interactions

29.03.2017 | Materials Sciences

Igniting a solar flare in the corona with lower-atmosphere kindling

29.03.2017 | Physics and Astronomy

As sea level rises, much of Honolulu and Waikiki vulnerable to groundwater inundation

29.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>