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 A novel socio-ecological approach helps identifying suitable wolf habitats
17.02.2017 | Universität Zürich

nachricht New, ultra-flexible probes form reliable, scar-free integration with the brain
16.02.2017 | University of Texas at Austin

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Tune your radio: galaxies sing while forming stars

21.02.2017 | Physics and Astronomy

Improved Speech Intelligibility and Automatic Speech-to-Text Conversion for Call Centers

21.02.2017 | Trade Fair News

36 big data research projects

21.02.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>