Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Evolutionary profits and losses

07.06.2010
The disruption of melatonin production in laboratory mouse strains represents an apparent evolutionary advantage in terms of reproductive development

Animal models can yield valuable insights into the biology of human disorders, although they can also introduce additional levels of complexity that may make it a challenge to experimentally untangle the bases for specific phenotypes.

Tadafumi Kato and Takaoki Kasahara of the RIKEN Brain Science Institute in Wako ran into such a challenge in their attempts to characterize abnormalities in the activity of melatonin, a hormone that fine-tunes the circadian rhythms that establish an organism’s day–night cycle, in their mouse model of bipolar disorder. “Since early times, researchers and psychiatrists have believed that melatonin has something to do with mood disorders, because many patients experience sleep disturbance and light therapy is used effectively in the treatment of seasonal affective disorder,” says Kasahara. However, they quickly found their efforts thwarted by the utter absence of melatonin from their laboratory mice.

Filling in the blanks

Indeed, a growing body of evidence suggests that several strains of laboratory mice—including the C57BL/6J (B6J) line used by Kato and Kasahara—are deficient in the production of melatonin, a process that depends on the sequential action of two enzymes: arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole O-methyltransferase (HIOMT).

Scientists have successfully identified the mouse Aanat gene, and have even uncovered an inactivating mutation within this gene in B6J mice. However, even with high-quality mouse genome sequence data available, nobody has yet succeeded in tracking down its partner, Hiomt. “I studied the mechanism of circadian clocks when I was a PhD student, and I heard that mouse Hiomt was really enigmatic,” recalls Kasahara, “and even after being away from the field for about six years, I became aware that mouse Hiomt still had not been identified.”

This is no longer the case, thanks to an extensive analysis of the mouse genome by Kato, Kasahara and colleagues. Using the rat HIOMT protein sequence as a basis for comparison they have finally managed to uncover this mysterious gene and have thereby revealed why it has remained hidden from scientists for so long.

Notably, mouse HIOMT bears only limited resemblance to its counterparts in other species, with an amino acid sequence that is less than 70% identical to that of the rat protein. Furthermore, this gene was likely masked by its residence within the pseudoautosomal region (PAR), a poorly characterized stretch of DNA within the sex chromosomes that enables them to efficiently ‘pair up’ and undergo recombination during meiosis. “The PAR contains extremely repetitive sequences and high guanine-cytosine content, both of which make it difficult to sequence using either traditional or next-generation sequencing methods,” says Kasahara.

Developmental consequences

Closer analysis of the sequence of this gene revealed two notable sequence variations in B6J mice relative to MSM animals—a strain derived more recently from wild mice that exhibits normal melatonin production. Both of these changes affect the amino acid sequence of the encoded protein, and the investigators showed that each mutation leads to a strong reduction in HIOMT levels. These mutations also proved to be widespread among a variety of other inbred mouse strains, including several lines commonly employed in laboratory research.

Kato, Kasahara and colleagues also noted that although this HIOMT deficiency appears to have a limited impact on circadian behaviors, it has a clear effect on gonadal development; melatonin-deficient animals with the B6J versions of the Hiomt and/or Aanat genes exhibited significantly greater testicular growth than their melatonin-producing counterparts. Conversely, in experiments with ICR mice, another melatonin-deficient strain, the researchers showed that treatment with melatonin was associated with a reduction in testicular weight.

These findings are in keeping with other data showing a vital link between melatonin and reproductive development—including observations in human patients. “Children with little or no melatonin due to pineal tumors often show premature sexual maturation,” says Kasahara.

Evolution in a cage

Because these defects appear to be specifically prevalent among cultivated strains of laboratory mice, it appears likely that there is some manner of selection taking place that favors the emergence of strains with reduced melatonin levels and accelerated reproductive development—even if this evolution was unintentional and, until now, invisible. This finding is supported by similar research in domesticated chickens, which has spotlighted the emergence of other gene variations that may potentially influence the same developmental pathway. “One of the most intriguing [variants] is found in the gene encoding the receptor for thyroid-stimulating hormone, because TSH and melatonin are closely related in seasonal breeding,” says Kasahara.

These findings could also have potential implications for previous animal studies that have investigated circadian rhythms, given that much of this research has been conducted in B6J and other inbred strains. For example, one recent study has shown that the circadian rhythm defects observed in the widely used B6J-derived Clock mutant mice are markedly diminished in the presence of normal levels of melatonin3.

These findings will closely inform future work from Kasahara and Kato, who are in the process of engineering a melatonin-producing B6J strain for use in their future investigations of mood disorders. However, Kasahara also suggests that conventional laboratory strains in general may be too interbred for their own good. “Our B6J mouse model for mood disorder has many phenotypes similar to bipolar disorder, but they don’t get manic spontaneously,” he says. “I hypothesize that laboratory mice have lost their potential to develop manic or aggressive episodes, and we are consequently using wild-derived mice, which are very aggressive, alert and agile in order to study these disorders.”

About the Researcher

Takaoki Kasahara

Takaoki Kasahara was born in Fukui, Japan, in 1972. He graduated from the College of Arts and Sciences, The University of Tokyo, in 1996. He studied the molecular mechanism underlying the phase shifting of circadian rhythms by light when he was a PhD student. After he obtained his PhD in 2001 from the University of Tokyo, he joined the Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute. He has been studying the pathophysiology of mood disorders and developing mouse models for these disorders. His mouse model for bipolar disorder was reviewed in the premier issue of RIKEN RESEARCH 1, 10 (2006). He was a Special Postdoctoral Researcher (RIKEN) from 2003 to 2006 and is now a Deputy Team Leader.

Journal information
1. Kasahara, T., Abe, K., Mekada, K., Yoshiki, A. & Kato, T. Genetic variation of melatonin productivity in laboratory mice under domestication. Proceedings of the National Academy of Sciences USA 107, 6412–6417 (2010)
2. Rubin, C.-J., Zody, M.C., Eriksson, J., Meadows, J.R.S., Sherwood, E., Webster, M.T., et al. Whole-genome resequencing reveals loci under selection during chicken domestication. Nature 464, 587-91 (2010)

3. Shimomura, K., Lowrey, P.L., Vitaterna, M.H., Buhr, E.D., Kumar, V., Hanna, P., Omura, C., Izumo, M., Low, S.S., Barrett, R.K. et al. Genetic suppression of the circadian Clock mutation by the melatonin biosynthesis pathway. Proceedings of the National Academy of Sciences USA published online, 19 April 2010 (doi: 10.1073/pnas.1004368107)

gro-pr | Research asia research news
Further information:
http://www.rikenresearch.riken.jp/eng/hom/6307
http://www.researchsea.com

More articles from Life Sciences:

nachricht Scientists discovered 20 new gnat species in Brazil
24.09.2018 | Estonian Research Council

nachricht Brought to light – chromobodies reveal changes in endogenous protein concentration in living cells
21.09.2018 | NMI Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Scientists present new observations to understand the phase transition in quantum chromodynamics

The building blocks of matter in our universe were formed in the first 10 microseconds of its existence, according to the currently accepted scientific picture. After the Big Bang about 13.7 billion years ago, matter consisted mainly of quarks and gluons, two types of elementary particles whose interactions are governed by quantum chromodynamics (QCD), the theory of strong interaction. In the early universe, these particles moved (nearly) freely in a quark-gluon plasma.

This is a joint press release of University Muenster and Heidelberg as well as the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt.

Then, in a phase transition, they combined and formed hadrons, among them the building blocks of atomic nuclei, protons and neutrons. In the current issue of...

Im Focus: Patented nanostructure for solar cells: Rough optics, smooth surface

Thin-film solar cells made of crystalline silicon are inexpensive and achieve efficiencies of a good 14 percent. However, they could do even better if their shiny surfaces reflected less light. A team led by Prof. Christiane Becker from the Helmholtz-Zentrum Berlin (HZB) has now patented a sophisticated new solution to this problem.

"It is not enough simply to bring more light into the cell," says Christiane Becker. Such surface structures can even ultimately reduce the efficiency by...

Im Focus: New soft coral species discovered in Panama

A study in the journal Bulletin of Marine Science describes a new, blood-red species of octocoral found in Panama. The species in the genus Thesea was discovered in the threatened low-light reef environment on Hannibal Bank, 60 kilometers off mainland Pacific Panama, by researchers at the Smithsonian Tropical Research Institute in Panama (STRI) and the Centro de Investigación en Ciencias del Mar y Limnología (CIMAR) at the University of Costa Rica.

Scientists established the new species, Thesea dalioi, by comparing its physical traits, such as branch thickness and the bright red colony color, with the...

Im Focus: New devices based on rust could reduce excess heat in computers

Physicists explore long-distance information transmission in antiferromagnetic iron oxide

Scientists have succeeded in observing the first long-distance transfer of information in a magnetic group of materials known as antiferromagnets.

Im Focus: Finding Nemo's genes

An international team of researchers has mapped Nemo's genome

An international team of researchers has mapped Nemo's genome, providing the research community with an invaluable resource to decode the response of fish to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

"Boston calling": TU Berlin and the Weizenbaum Institute organize a conference in USA

21.09.2018 | Event News

One of the world’s most prominent strategic forums for global health held in Berlin in October 2018

03.09.2018 | Event News

4th Intelligent Materials - European Symposium on Intelligent Materials

27.08.2018 | Event News

 
Latest News

Matter falling into a black hole at 30 percent of the speed of light

24.09.2018 | Physics and Astronomy

NASA balloon mission captures electric blue clouds

24.09.2018 | Earth Sciences

New way to target advanced breast cancers

24.09.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>