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

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Turmoil in sluggish electrons’ existence

An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.

We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...

Im Focus: Wafer-thin Magnetic Materials Developed for Future Quantum Technologies

Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.

Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...

Im Focus: World's thinnest hologram paves path to new 3-D world

Nano-hologram paves way for integration of 3-D holography into everyday electronics

An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...

Im Focus: Using graphene to create quantum bits

In the race to produce a quantum computer, a number of projects are seeking a way to create quantum bits -- or qubits -- that are stable, meaning they are not much affected by changes in their environment. This normally needs highly nonlinear non-dissipative elements capable of functioning at very low temperatures.

In pursuit of this goal, researchers at EPFL's Laboratory of Photonics and Quantum Measurements LPQM (STI/SB), have investigated a nonlinear graphene-based...

Im Focus: Bacteria harness the lotus effect to protect themselves

Biofilms: Researchers find the causes of water-repelling properties

Dental plaque and the viscous brown slime in drainpipes are two familiar examples of bacterial biofilms. Removing such bacterial depositions from surfaces is...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

AWK Aachen Machine Tool Colloquium 2017: Internet of Production for Agile Enterprises

23.05.2017 | Event News

Dortmund MST Conference presents Individualized Healthcare Solutions with micro and nanotechnology

22.05.2017 | Event News

Innovation 4.0: Shaping a humane fourth industrial revolution

17.05.2017 | Event News

 
Latest News

Supercomputing helps researchers understand Earth's interior

23.05.2017 | Earth Sciences

Study identifies RNA molecule that shields breast cancer stem cells from immune system

23.05.2017 | Life Sciences

Turmoil in sluggish electrons’ existence

23.05.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>