Newswise DALLAS Aug. 7, 2020 UT Southwestern scientists have developed a genetically engineered mouse and imaging system that lets them visualize fluctuations in the circadian clocks of cell types in mice. The method, described online in the journal Neuron, gives new insight into which brain cells are important in maintaining the bodys master circadian clock. But they say the approach will also be broadly useful for answering questions about the daily rhythms of cells throughout the body.
This is a really important technical resource for advancing the study of circadian rhythms, says study leader Joseph Takahashi, Ph.D., chair of the department of neuroscience at UT Southwestern Medical Center, a member of UT Southwesterns Peter ODonnell Jr. Brain Institute, and an investigator with the Howard Hughes Medical Institute (HHMI). You can use these mice for many different applications.
Nearly every cell in humans and mice has an internal circadian clock that fluctuates on a roughly 24-hour cycle. These cells help dictate not only hunger and sleep cycles, but biological functions such as immunity and metabolism. Defects in the circadian clock have been linked to diseases including cancer, diabetes, and Alzheimers, as well as sleep disorders. Scientists have long known that a small part of the brain called the suprachiasmatic nucleus (SCN) integrates information from the eyes about environmental light and dark cycles with the bodys master clock. In turn, the SCN helps keep the rest of the cells in the body in sync with each other.
What makes the SCN a very special kind of clock is that its both robust and flexible, says Takahashi. Its a very strong pacemaker that doesnt lose track of time, but at the same time can shift to adapt to seasons, changing day lengths, or travel between time zones.
To study the circadian clock in both the SCN and the rest of the body, Takahashis research group previously developed a mouse that had a bioluminescent version of PER2 one of the key circadian proteins whose levels fluctuate over the course of a day. By watching the bioluminescence levels wax and wane, the researchers could see how PER2 cycled throughout the animals bodies during the day. But the protein is present in nearly every part of the body, sometimes making it difficult to distinguish the difference in circadian cycles between different cell types mixed together in the same tissue.
If you observe a brain slice, for instance, almost every single cell has a PER2 signal, so you cant really distinguish where any particular PER2 signal is coming from, says Takahashi.
In the new work, the scientists overcame this problem by turning to a new bioluminescence system that changed color from red to green only in cells that expressed a particular gene known as Cre. Then, the researchers could engineer mice so that Cre, which is not naturally found in mouse cells, was only present in one cell type at a time.
To test the utility of the approach, Takahashi and his colleagues studied two types of cells that make up the brains SCN arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) cells. In the past, scientists have hypothesized that VIP neurons hold the key to keeping the rest of the SCN synchronized.
When the research team looked at VIP neurons expressing Cre in just those cells, so that PER2 luminesced green in VIP cells, while red elsewhere they found that removing circadian genes from the neurons had little overall effect on the circadian rhythms of the VIP neurons, or the rest of the SCN. Even when VIP neurons no longer had a functioning clock, the rest of the SCN behaved essentially the same, explains Yongli Shan, Ph.D., a UTSW research scientist and lead author of the study. Nearby cells were able to signal to the VIP neurons to keep them in sync with the rest of the SCN, he says.
When they repeated the same experiment on AVP neurons, however removing key clock genes not only did AVP neurons themselves show disrupted rhythms, but the entire SCN stopped synchronously cycling on its usual 24-hour rhythm.
What this showed us was that the clock in AVP neurons is really essential for the synchrony of the whole SCN network, says Shan. Thats a surprising result and somewhat counterintuitive, so we hope it leads to more work on AVP neurons going forward.
Takahashi says other researchers who study circadian rhythms have already requested the mouse line from his lab to study the daily cycles of other cells. The mice might allow scientists to hone in on the differences in circadian rhythms between cell types within a single organ, or how tumor cells cycle differently than healthy cells, he says.
In all sorts of complex or diseased tissues, this can let you see which cells have rhythms and how they might be similar or different from the rhythms of other cell types.
Takahashi holds the Loyd B. Sands Distinguished Chair in Neuroscience.
Other UTSW researchers who contributed to this study were Yan Li, Mariko Izumo, Kimberly Cox, Byeongha Jeong, and Seung-Hee Yoo, who is now at UT Health Science Center in Houston. Collaborators were John Abel and Francis Doyle of Harvard Medical School and David Olson of the University of Michigan.
This research was supported by funds from the HHMI, the National Institutes of Health (R01 NS106657, R01 GM114424, T32-HLO9701, F32-AG064886), and The Welch Foundation (AU-1971-20180324).
About UTSouthwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes, and includes 24 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,500 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.
Link:
Pinpointing The Cells That Keep The Bodys Master Circadian Clock Ticking - Newswise
- IOM not webcast today. Why Not? - November 8th, 2009 [November 8th, 2009]
- National Academies skeptical at Best. - November 8th, 2009 [November 8th, 2009]
- Some Confusion Exists - November 8th, 2009 [November 8th, 2009]
- Why DTC Genomics IS Medicine. - November 8th, 2009 [November 8th, 2009]
- First Mari, Now Linda. Who's next? - November 8th, 2009 [November 8th, 2009]
- Is it true? - November 8th, 2009 [November 8th, 2009]
- Re-Reviewing the National Academies - November 8th, 2009 [November 8th, 2009]
- The problem with nonclinicians....... - November 8th, 2009 [November 8th, 2009]
- Crazy Night of Emails to Government - November 8th, 2009 [November 8th, 2009]
- Adrienne Carlson's Personalized Medicine. - November 8th, 2009 [November 8th, 2009]
- Tell Me, How do you feel now? Sherpa's RX - November 8th, 2009 [November 8th, 2009]
- This Just In. 23andMe to go to GPs. I love my readers!! - November 8th, 2009 [November 8th, 2009]
- Sorry so long away - November 8th, 2009 [November 8th, 2009]
- 2D6 Rears its ugly head..... - November 8th, 2009 [November 8th, 2009]
- Ok, Fine, Back to Plavix - November 8th, 2009 [November 8th, 2009]
- Kaiser a protoype for Collins' Aim - November 8th, 2009 [November 8th, 2009]
- A few months late to the party.... - November 8th, 2009 [November 8th, 2009]
- Stated Another Way....... - November 8th, 2009 [November 8th, 2009]
- Excuse Me? Harvard and Navigenics? WTF? - November 8th, 2009 [November 8th, 2009]
- Follow up to Yesterday's WTF? Harvard, Navi? and Pfizer??? - November 8th, 2009 [November 8th, 2009]
- Did you get your kit? Thanks Dr. Rob from MedCo - November 8th, 2009 [November 8th, 2009]
- Gluco...Wha? Parkinson's Disease and Glucocerebrosidase mutations. - November 8th, 2009 [November 8th, 2009]
- Away and now back, What did I miss???? 23andme layoffs? Selling Genomes for cheap up next! - November 8th, 2009 [November 8th, 2009]
- Change IS Needed. I agree with William, sometimes. - November 8th, 2009 [November 8th, 2009]
- Good Enough Science? Apparently so at 23andme - November 8th, 2009 [November 8th, 2009]
- Long QT Syndrome, location matters - December 13th, 2009 [December 13th, 2009]
- Congratulations Generation Health. Nice pick up! - December 13th, 2009 [December 13th, 2009]
- An argument 23andSerge can't win...23andme but not medicine - December 13th, 2009 [December 13th, 2009]
- Stop. Breathe. Repeat. An analysis of the direction of DTC Genomics Field. - December 13th, 2009 [December 13th, 2009]
- Hey DTC genomics, Stay Private, Stay Alive, Go Public and Die - December 13th, 2009 [December 13th, 2009]
- You can't have it both way. Either scared your genome is sold off or not. - December 13th, 2009 [December 13th, 2009]
- 15 Days Away Gives Time for Perspective. - December 13th, 2009 [December 13th, 2009]
- What about the SACGHS registry? Another missed opportunity? - December 13th, 2009 [December 13th, 2009]
- AJHG is in and my Favorite Muin is in it! But He Is NOT the Father! - December 13th, 2009 [December 13th, 2009]
- Navigenics for 23andMe prices? - December 18th, 2009 [December 18th, 2009]
- Lp(a) Maybe there's something there that wasn't there before? - December 24th, 2009 [December 24th, 2009]
- Another Year, Another Bankruptcy - December 31st, 2009 [December 31st, 2009]
- 5 Technologies going bye bye in this decade? - January 6th, 2010 [January 6th, 2010]
- Hackers, HITECH and HIPAA in DTC Genomics, Oh My! - January 7th, 2010 [January 7th, 2010]
- Personal Genomics Flop.....big Belly Flop! - January 8th, 2010 [January 8th, 2010]
- Gotta Love It. Even the daycare....... - January 11th, 2010 [January 11th, 2010]
- Congratulations Navigenics. You ARE a clinical lab! Uh-Oh... - January 12th, 2010 [January 12th, 2010]
- CETP, Jewish Centenarians and Alzheimers - January 14th, 2010 [January 14th, 2010]
- Enter the "Not" DTC Genomics Rep - January 17th, 2010 [January 17th, 2010]
- Why Dr. Vanier's Navigenics appointment is good for PM - January 22nd, 2010 [January 22nd, 2010]
- Holy Crap! MedCo Follows in CVS footsteps - February 3rd, 2010 [February 3rd, 2010]
- FDA, Warfarin, still not as sexy to me. - February 5th, 2010 [February 5th, 2010]
- Hype, Hype, Hype from a single study. - February 11th, 2010 [February 11th, 2010]
- I love my readers, even Renata M! - February 17th, 2010 [February 17th, 2010]
- How can insurers use DTC genomics to profile? - February 17th, 2010 [February 17th, 2010]
- 9p21.....ahem. Paynter et.al. Smackdown. Again. - February 18th, 2010 [February 18th, 2010]
- Hey! It's Pete Hulick! Are you Going to GET? - February 19th, 2010 [February 19th, 2010]
- I was wrong......AHEM - February 28th, 2010 [February 28th, 2010]
- G2C2, finally a tool for genomic education! - March 2nd, 2010 [March 2nd, 2010]
- Just 4 million? What 23andMe is worth. - March 5th, 2010 [March 5th, 2010]
- What a difference a year makes - March 9th, 2010 [March 9th, 2010]
- ........DTC Genomic Medicine? - March 12th, 2010 [March 12th, 2010]
- The FDA, 2c19 and the ACC - March 13th, 2010 [March 13th, 2010]
- The problem with Comparative Whole Genomics...... - March 13th, 2010 [March 13th, 2010]
- BRCA testing by 23andME is the same as Myriad Genetics. - March 15th, 2010 [March 15th, 2010]
- The Argument Against DTC Genomics Marketing and such - March 16th, 2010 [March 16th, 2010]
- A moment of Clarity. Some DTCG is not bad. - March 18th, 2010 [March 18th, 2010]
- SNPs for breast cancer risk? It Depends. - March 18th, 2010 [March 18th, 2010]
- How can MDVIP use Navigenics Test for Medicine? - March 18th, 2010 [March 18th, 2010]
- Why did P&G invest in Navigenics? - March 23rd, 2010 [March 23rd, 2010]
- PGx in DTCG? Doesn't stand up to Useful testing. - March 25th, 2010 [March 25th, 2010]
- End of Gene Patents? - March 29th, 2010 [March 29th, 2010]
- Sherpa Accepting Chief Medical Officership - April 3rd, 2010 [April 3rd, 2010]
- The Rumors of My Death........ - April 20th, 2010 [April 20th, 2010]
- Happy DNA Day! - April 25th, 2010 [April 25th, 2010]
- 99 USD, DNA day and patient letters - April 25th, 2010 [April 25th, 2010]
- 2C19, Navigenics and Clinical Reality. - May 1st, 2010 [May 1st, 2010]
- Coriell Personalized Medicine Collaborative rising - May 7th, 2010 [May 7th, 2010]
- Personal Genomes in Clinical Care. Quake paper is a waste! - May 11th, 2010 [May 11th, 2010]
- Personal Genomes in Clinical Care. Quake paper Falls Short! - May 13th, 2010 [May 13th, 2010]
- Last post edited by Drew - May 13th, 2010 [May 13th, 2010]
- GateKeeper? FCUK U! - May 13th, 2010 [May 13th, 2010]
- GateKeeper? F! U! - May 15th, 2010 [May 15th, 2010]
- Potential of genomic medicine, LOST - May 19th, 2010 [May 19th, 2010]
- How Bad Can a House Investigation be for DTC Genomics? - May 20th, 2010 [May 20th, 2010]