Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New Role Discovered for Molecule Important in Development of Pancreas

14.07.2009
Implications for New Diabetes Treatments

For years researchers have been searching for a way to treat diabetics by reactivating their insulin-producing beta cells, to no avail. Now, they may be one step closer.

A protein, whose role in pancreatic development has long been recognized, has been discovered to play an additional and previously unknown regulatory role in the development of cells in the immature endocrine system. These cells ultimately give rise to pancreatic islet cells, which include beta cells.

By carefully defining the developmental steps and genetic circuits that lead to mature beta cells, researchers may be able to one day mimic these developmental processes, thereby facilitating beta-cell growth in the lab, and eventually, new therapies. The findings appear in the July 2009 issue of the Journal of Clinical Investigation.

“The protein, Pdx1, is a pivotal molecule in the regulation of beta-cell development and we hope this type of information could help in efforts to generate beta-cell replacements for the treatment of diabetes," says senior author Doris Stoffers, MD, PhD, Associate Professor of Medicine at the University of Pennsylvania School of Medicine. Stoffers is also a member of the Institute for Diabetes, Obesity, and Metabolism at Penn.

Pdx1 is a key regulator of pancreatic development and adult beta-cell function. For example, loss of a single copy of Pdx1 in mice leads to diabetes; loss of two copies leads to a complete failure of the pancreas to form. This new research expands the role of Pdx1 in beta-cell biology in the developing embryo.

Ultimately, Stoffers says, these findings could help researchers intent on developing cell-based therapeutic approaches to diabetes – though such advances are a long way off. Both type 1 and type 2 diabetes are caused by a loss of insulin-producing beta cells. In theory, transplantation of fresh beta cells should halt the disease, yet researchers have not yet been able to generate these cells in the lab at high efficiency, whether from embryonic stem cells or by reprogramming other mature cell types.

“The prevailing view is if we understood how the process occurs normally, we might be able to apply that information to faithfully and efficiently push the cells down the pathway to ultimately generate beta cells that may be used clinically,” she says.

The new findings represent a previously unknown role for Pdx1. Endocrine precursor cell development is controlled by a DNA-binding transcription factor called neurogenin-3 (Ngn3). Ngn3, in turn, is regulated by four additional proteins: Sox9, Foxa2, Hnf6, and Hnf1b. In short, this study found that Pdx1 binds directly to the Ngn3 gene to orchestrate gene expression with these proteins.

Specifically, Stoffers was curious about the function of one end of the Pdx1 protein – the C terminus – whose role in beta-cell development was not known – and yet is mutated in certain diseases. Her team, led by MD-PhD candidate Jennifer Oliver-Krasinski, developed mice that lacked the C terminus, essentially with a shortened Pdx1 protein.

The team found that when both copies of the Pdx1 gene were truncated at the C terminus, the pancreas formed, but the mice quickly developed diabetes. When they investigated why, they found that these mice were deficient in all endocrine cells, including beta cells.

“That led us to conclude the defect was at an early cell, or precursor, stage,” Stoffers says – specifically, in the formation of Ngn3-expressing endocrine progenitor cells.

Further molecular characterization of these mutant mice led the team to conclude that Pdx1 is a master regulator of the development of endocrine cell precursors. Pdx1 binds directly to the Ngn3 gene, controlling its expression; it does this by forming a molecular complex with the protein Hnf6, which is mediated by the Pdx1 C terminus. Pdx1 also binds directly to and controls the expression of two additional endocrine cell genes, Hnf1b and Foxa2.

“Pdx1 not only directly regulates Ngn3, it also indirectly regulates it by controlling the regulatory network of Sox9, Foxa2, Hnf6, and Hnf1b,” she explains.

The most immediate implications of the findings also suggest a molecular mechanism for why those individuals who harbor mutations in Pdx1 get diabetes. If Pdx1 controls Ngn3, and Ngn3 governs endocrine progenitor cell formation, then loss of Pdx1 should result in a loss of endocrine lineages, including beta cells.

That appears to be the case in mice. Now, says Stoffers, the question is: Does this regulatory pathway look and act the same in humans as in mice? “It is likely that the mechanisms are the same, but we would like to directly test that,” concludes Stoffers.

Co-authors in addition to Stoffers and Oliver-Krasinski are Margaret Kasner, Juxiang Yang, Michael F. Crutchlow, Anil Rustgi, and Klaus Kaestner, all from Penn.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases.

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #3 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to the National Institutes of Health, received over $366 million in NIH grants (excluding contracts) in the 2008 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center, named one of the nation’s “100 Top Hospitals” for cardiovascular care by Thomson Reuters. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.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 >>>