Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecular Path from Internal Clock to Cells Controlling Rest and Activity Revealed in Penn Study

08.02.2012
The molecular pathway that carries time-of-day signals from the body's internal clock to ultimately guide daily behavior is like a black box, says Amita Sehgal, PhD, the John Herr Musser Professor of Neuroscience and Co-Director, Comprehensive Neuroscience Center, at the Perelman School of Medicine, University of Pennsylvania.

Now, new research from the Sehgal lab is taking a peek inside, describing a molecular pathway and its inner parts that connect the well-known clock neurons to cells governing rhythms of rest and activity in fruit flies. Sehgal is also an investigator with the Howard Hughes Medical Institute.

The other co-author on the study is Wenyu Luo, PhD, a Penn doctoral student who recently defended her dissertation. The findings, which will be featured on the cover of the February 17th issue of Cell, are published online this week.

"Most colleagues would say that we have some understanding of how the clock works and how it is synchronized with light,” says Sehgal. “But we are just beginning to get a glimpse of how the clock drives behavior in the rest of an organism's systems."

Prying the Black Box Open

Normally, flies have a robust rhythm of being active during daylight hours and quiet during the night. Sehgal and Luo essentially found that a microRNA (miRNA) named miR-279 acts through the JAK/STAT pathway to regulate locomotor activity rhythms through a daily cycling of proteins.

An miRNA is a tiny piece of RNA - a little over 20 bases (DNA building blocks) in length -- that binds to matching pieces of messenger RNA, thereby tying it up and decreasing the production of the corresponding protein.

They found that in mutant flies in which miR-279 was either overexpressed or deleted -- causing high levels or low levels of JAK/STAT signaling -- the flies wake and sleep at random intervals. The flies showed no discernible pattern of activity. Therefore, the investigators concluded that a mid-range level of JAK/STAT activity is necessary to maintain the flies' normal pattern. In fact, they found that STAT activity displays a daily rhythm.

Part of the Clock Circuitry

Oscillations of the clock protein PERIOD are normal in clock pacemaker neurons lacking miR-279, suggesting that miR-279 acts downstream of the clock neurons. The team identified the JAK/STAT partner, a protein called Upd, as a target of miR-279. They also showed that knocking down Upd rescues the off-rhythm behavior of the miR-279 mutant flies.

In addition, in brains of mutant flies stained to identify circadian proteins, they found that the central clock neurons project their axons into the vicinity of Upd-expressing neurons, providing a possible physical connection by which the central clock could regulate JAK/STAT signaling to control rest and activity rhythms.

With these findings, the team proposed a model in which the central clock affects the cycle of secretion of the Upd protein from cells. "Upd may act like a time-release capsule," explains Sehgal. "To maintain a typical rest:activity rhythm, the level of Upd has to be just right."

The mRNA levels of Upd in neurons are kept low by miR-279. Upd may rhythmically activate a receptor, Dome, in a third cell, which would lead to daily oscillations of JAK/STAT activity and ultimately to the rest:activity rhythm.

The direct clinical implications of knowing the players in this complicated pathway are not yet clear. But we might be able to conclude, suggests Sehgal, that, if these mechanisms are conserved in humans, then disorders in which the JAK-STAT pathway isn't working properly, as in some immune disorders, physicians might also see problems with patients' sleep-wake cycle.
These findings also provide researchers with a handle on the neural circuit that generates rest:activity behavior in Drosophila. The ultimate goal of many neurobiologists is to trace the entire molecular and cellular pathway that produces a specific behavior. This study is a step towards that goal.
The work was supported by NIH grants 1-R560NS-048471 and 2R01NS04847.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4 billion enterprise.

Penn's Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools and among the top 10 schools for primary care. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $507.6 million awarded in the 2010 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top 10 hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital – the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2010, Penn Medicine provided $788 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu
http://www.uphs.upenn.edu/news/News_Releases/2012/02/internal-clock-black-box/

More articles from Life Sciences:

nachricht Study reveals how bacteria build essential carbon-fixing machinery
09.07.2020 | University of Liverpool

nachricht Stress testing 'coral in a box'
09.07.2020 | University of Konstanz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: The spin state story: Observation of the quantum spin liquid state in novel material

New insight into the spin behavior in an exotic state of matter puts us closer to next-generation spintronic devices

Aside from the deep understanding of the natural world that quantum physics theory offers, scientists worldwide are working tirelessly to bring forth a...

Im Focus: Excitation of robust materials

Kiel physics team observed extremely fast electronic changes in real time in a special material class

In physics, they are currently the subject of intensive research; in electronics, they could enable completely new functions. So-called topological materials...

Im Focus: Electrons in the fast lane

Solar cells based on perovskite compounds could soon make electricity generation from sunlight even more efficient and cheaper. The laboratory efficiency of these perovskite solar cells already exceeds that of the well-known silicon solar cells. An international team led by Stefan Weber from the Max Planck Institute for Polymer Research (MPI-P) in Mainz has found microscopic structures in perovskite crystals that can guide the charge transport in the solar cell. Clever alignment of these "electron highways" could make perovskite solar cells even more powerful.

Solar cells convert sunlight into electricity. During this process, the electrons of the material inside the cell absorb the energy of the light....

Im Focus: The lightest electromagnetic shielding material in the world

Empa researchers have succeeded in applying aerogels to microelectronics: Aerogels based on cellulose nanofibers can effectively shield electromagnetic radiation over a wide frequency range – and they are unrivalled in terms of weight.

Electric motors and electronic devices generate electromagnetic fields that sometimes have to be shielded in order not to affect neighboring electronic...

Im Focus: Gentle wall contact – the right scenario for a fusion power plant

Quasi-continuous power exhaust developed as a wall-friendly method on ASDEX Upgrade

A promising operating mode for the plasma of a future power plant has been developed at the ASDEX Upgrade fusion device at Max Planck Institute for Plasma...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Contact Tracing Apps against COVID-19: German National Academy Leopoldina hosts international virtual panel discussion

07.07.2020 | Event News

International conference QuApps shows status quo of quantum technology

02.07.2020 | Event News

Dresden Nexus Conference 2020: Same Time, Virtual Format, Registration Opened

19.05.2020 | Event News

 
Latest News

Porous graphene ribbons doped with nitrogen for electronics and quantum computing

09.07.2020 | Physics and Astronomy

Record efficiency for printed solar cells

09.07.2020 | Power and Electrical Engineering

Rock 'n' control

09.07.2020 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>