Modeling psychiatric disorders in mice

One of the molecular causes of the behavioral and cognitive deficits observed in mice with a small chromosomal deletion has been identified, according to a study published online this week in Nature Genetics. The corresponding deletion in the human genome gives rise to a range of psychiatric disorders, and accounts for approximately 1–2% of cases of schizophrenia in the general population.

Deletion of a small region on chromosome 22 is associated with anxiety, depression, attention-deficit hyperactivity disorder, autism, and deficits in working memory. Approximately 30% of the individuals carrying such a deletion eventually develop schizophrenia.

Maria Karayiorgou, Joseph Gogos and colleagues generated a model in which the corresponding region was deleted in the mouse genome. Mice carrying a single deletion show a range of behavioral and cognitive deficits that mimic some aspects of the human syndrome. Of particular interest is the increased expression of precursors of the small regulatory RNAs known as microRNAs in the brains of the mutant mice. The authors went on to show that loss of one of genes in the deleted region, Dgcr8, is responsible for this increased abundance of precursors, as the normal role of Dgcr8 is to process them into mature microRNAs. By generating mice that have only one copy of Dgcr8, the authors showed that this mutation by itself results in at least some of the deficits observed in mice with the deletion of the surrounding region.

Although the specific downstream targets of altered microRNA expression in the brain are not yet known, the authors suggest these findings could have general implications for understanding the genetic basis of psychiatric disorders.

Author contacts:
Maria Karayiorgou (Columbia University Medical Center, New York, NY, USA)
Tel: +1 212 568 4189; E-mail: mk2758@columbia.edu

Joseph Gogos (Columbia University Medical Center, New York, NY, USA)
Tel: +1 212 305 0744; E-mail: jag90@columbia.edu

Stem-cell regeneration of the breast relies on adhesion


Interaction of basal stem cells in the breast with their cellular environment is crucial for their function, and helps towards the regeneration of the mammary glands during pregnancy, reports a paper online this week in Nature Cell Biology.

The basal stem cells of the breast are enriched in proteins called integrins that mediate contact with the extracellular matrix surrounding the cells. Marina Glukhova and colleagues show that expression of beta 1 integrin in the basal cells is essential for the regenerative potential of these stem cells and for proper development of the mammary gland during pregnancy.

Deletion of the beta 1 integrin gene from the basal layer of mouse mammary tissue led to an abnormal ductal branching pattern in the mammary gland during pregnancy, which results in the regenerative potential of the mammary tissue stem cells being abolished, leading to a dysfunctional gland. In basal stem cells lacking beta 1 integrin, cells divide abnormally and this results in the altered branching pattern.

The environment that surrounds most stem cells, the stem cell niche, is known to be important for a number of stem cells. However, our understanding of stem cell niches remains patchy. These findings establish a central role of direct interaction between basal stem cells and their extracellular matrix in the maintenance of the mammary stem-cell population.

Author contact:
Marina Glukhova (CNRS-Institut Curie Research, Paris, France)
Tel: +33 1 42 34 63 33; E-mail: Marina.Glukhova@curie.fr

The origins of the modern tomato


Scientists have identified a genetic mutation that acts as a major contributor to the extreme fruit size associated with the modern tomato, according to a study.

Modern cultivated tomatoes produce fruit as much as 1,000 times larger than their wild progenitors. One clear reason for the increase in tomato size during its domestication is the increased number of carpels – organs – which determines the final number of compartments in the fruit.

Steven Tanksley and colleagues crossed lines of tomatoes with either high or low compartment number, and carried out genetic mapping studies to identify the gene or genes responsible for the variation in carpel number. They identified an insertion of 6–8 kilobases in a gene they call fas only in the tomatoes with high compartment number. Expression of the gene is reduced in the developing flower buds in tomatoes carrying the insertion. A survey of 30 different lines of cerasiforme, the wild form of tomato thought to be related to the smaller progenitors, showed that none carried the insertion.

As the insertion is found exclusively in modern cultivated tomatoes, the authors suggest that the mutation occurred recently in tomato domestication, and then spread rapidly as a result of selection for larger fruit.

Author contact:
Steven Tanksley (Cornell University, Ithaca, NY, USA)
Tel: +1 607 255 1673; E-mail: sdt4@cornell.edu

The planets: Mysteries surrounding the ‘butterscotch’ planet’s equator


Saturn, the second largest planet in the Solar System, is easily spotted because of the brightness of the rings around its equator. Two companion papers in this week’s Nature report on features of its atmosphere, one using data collected by the Cassini mission and the other from over two decades of ground-based observations.

The equatorial stratospheres of Earth and Jupiter oscillate more or less periodically on timescales of about two and four years, respectively. By analysing infrared observations from the Cassini probe, Thierry Fouchet and colleagues discovered that Saturn has an equatorial oscillation like Earth's and Jupiter's, as well as a mid-latitude subsidence that may be associated with the equatorial motion. Glenn Orton and co-workers’ ground-based observations of Saturn's stratospheric emission reveal a similar oscillation.

The period of the oscillation is approximately 15 terrestrial years, which is roughly half of Saturn's year, suggesting the influence of seasonal forcing —rather like the Earth's semi-annual oscillation.

CONTACT

Glenn Orton (Jet Propulsion Laboratory, Pasadena, CA, USA) Author paper [3]
Tel: +1 818 354 2460; E-mail: Glenn.Orton@jpl.nasa.gov

Thierry Fouchet (Observatoire de Paris, Meudon, France) Author paper [4]
Tel: +33 1 45 07 71 11; E-mail: Thierry.Fouchet@obspm.fr

Timothy Dowling (University of Louisville, KY, USA) N&V author
Tel: +1 502 852 3927; E-mail: dowling@louisville.ed

Genomes: Is it a bird, is it a mammal…?

The duck-billed platypus (Ornithorhynchus anatinus) is a truly unique animal, and its fascinating genome. Platypuses are monotremes with almost no close relatives alive on earth. Scientists just had to take a look at that genome, and now an international collaboration of researchers report its sequencing and analysis.

Famously considered a hoax when sent from Australia to European researchers in the nineteenth century, the platypus is an amalgam of reptilian, mammalian and unique characteristics that provide clues to the function and evolution of all mammalian genomes. Sequencing of the platypus genome has helped to uncover the following: the origins of genomic imprinting in vertebrates; platypus venom proteins were co-opted independently from the same gene families that provided reptile venom; milk protein genes are conserved; and immune gene family expansions are directly related to platypus biology. As well as providing an invaluable resource for comparative genomics, the sequence will be important for monotreme conservation.

CONTACT

Wesley Warren (Washington University School of Medicine, St Louis, MO, USA)
Tel: +1 314 286 1899; E-mail: wwarren@wustl.edu

Jennifer Marshall Graves (Australian National University, Canberra, Australia)
Tel: +61 261 252 492; E-mail: jenny.graves@anu.edu.au

Ewan Birney (The European Bioinformatics Institute, Cambridge, UK)
E-mail: birney@ebi.ac.uk

Developmental genetics: Starting out on the road to maleness

Growing up male is a genetic lifestyle decision — early in embryonic development, genes on the Y chromosome activate the development of specialized cells that ultimately become the testes. Without this ‘on switch’ for maleness, the developing gonads become ovaries by default and the embryo develops as a female.A study of mice now shows how the developing gonads start out on this road to maleness. In a paper geneticists Robin Lovell-Badge and Ryohei Sekido describe how a gene called Sry, carried on the Y chromosome, boosts another gene elsewhere in the genome that in turn governs the development of sperm-producing cells called Sertoli cells — a crucial component of the testes.By studying gene expression patterns in developing mouse embryos, the researchers deduced that Sry produces a protein that combines with another protein, steroidogenic factor 1 (SF1). This complex then binds to a DNA region that boosts the expression of another gene, Sox9, which controls a host of genes involved in sperm development.Elucidating this pathway not only reveals how maleness develops from the ‘default’ female developmental pathway; defects in this process may also explain how people who are genetically ‘male’ or ‘female’ end up developing the ‘wrong’ sexual anatomy.
contact:
Robin Lovell-Badge (National Institute for Medical Research, London, UK)Tel: +44 20 8816 2126;

Genetic susceptibility to obesity

Scientists have discovered genetic variants that increase the risk of obesity and insulin resistance in the general population, according to two studies published online this week in Nature Genetics. Until now only one locus (FTO) has been associated convincingly with increased risk of obesity.A consortium of investigators led by Mark McCarthy, Ines Barroso and Nicholas Wareham analyzed the genomes of more than 90,000 individuals and found that a variant near MC4R, encoding the melanocortin-4 receptor, increases susceptibility to obesity. Previous studies had shown that the melanocortin-4 receptor is expressed in neurons in the hypothalamus and is a key regulator of food intake and energy expenditure. Although it is unclear how this variant affects MC4R expression or function, the fact that mutations in the gene are known to cause rare cases of severe childhood obesity lends confidence to the association.In a separate study, Jaspal Kooner and colleagues carried out a genome-wide scan of several thousand individuals of Indian Asian or European ancestry, and identified a variant near MC4R as increasing risk of obesity and insulin resistance. The risk variant was more frequent in individuals of Indian Asian ancestry, which the authors suggest may account for the increased burden of obesity in Indian Asians.Author contacts:Mark McCarthy (University of Oxford, UK) Author paper [7]Tel: +44 1865 857 298; E-mail: mark.mccarthy@drl.ox.ac.ukInês Barroso (Wellcome Trust Sanger Institute, Hinxton, UK) Co-author paper [7]Tel: +44 1223 495 341; E-mail: ib1@sanger.ac.ukNicholas Wareham (Addenbrooke’s Hospital, Cambridge, UK) Co-author paper [7]Tel: +44 1223 330 315; E-mail: nick.wareham@mrc-epid.cam.ac.ukJaspal Kooner (Imperial College London, UK) Author paper [8]Tel: +44 20 8383 4751; E-mail: j.kooner@imperial.ac.uk

Obesity: Your number of fat cells stays constant in adulthood

number of fat cells, or adipocytes, in your body remains more or less constant throughout adulthood, a new study finds। The discovery suggests that the difference in the number of fat cells between lean and obese people is established in childhood, and then persists for life।The number of fat cells remains constant even in formerly obese adults who have lost significant amounts of weight, report researchers led by Kirsty Spalding, who studied fat samples from liposuction and abdominal reconstruction surgery in lean and obese volunteers। This reflects the fact that the level of obesity is determined by a combination of the number and size of fat cells, which can grow or shrink as fat from food is deposited in them।Although fat cell numbers remain constant during adulthood, this is a dynamic process of death and replenishment, Spalding and her colleagues report. Fat cells are replaced at the same rate that they die — roughly 10% every year. The researchers made their discovery by studying levels of radioactive isotopes in fat cells from people who had lived through the brief period of Cold War nuclear bomb testing from 1955 to 1963. People whose fat cells were deposited before the onset of testing nevertheless incorporated radioactive matter after, showing that their fat cells were being replenished.The fact that fat cells are constantly dying and being replaced could potentially offer an opportunity to develop new anti-obesity therapies, the researchers suggest.


Author contact:
Kirsty Spalding (Karolinska Institute, Stockholm, Sweden)Tel: +46 70 437 1542; E-mail:


kirsty.spalding@cmb.ki.se

The Hunt for the Kill Switch


The U.S. Department of Defense wants to know if chip makers are building remotely accessible kill switches into high-end microprocessors. These days, the U.S. military consumes only about 1 percent of the world's integrated circuits, and offshoring has begun to raise some alarms about the safety of the chips in the military's most mission-critical electronics.

Recognizing an enormous vulnerability, the DOD recently launched an extremely ambitious program to verify the integrity of the electronics that will underpin future additions to its arsenal. In December, the DOD's advanced-research wing released details about a three-year initiative it calls the Trust in Integrated Circuits program. The findings from the program could give the military--and defense contractors who make sensitive microelectronics like the weapons systems for the F-35--a guaranteed method of determining whether their chips have been compromised with a kill switch.

But how exactly would you kill an integrated switch, and for what purpose? In "The Hunt for the Kill Switch," IEEE Spectrum's Sally Adee reports on the methods that could kill a chip, the possible consequences, and the methods being devised to verify the Pentagon's most important microchips.(NewsWise)

Researchers Grow Heart and Blood Cells from Reprogrammed Skin Cells



Stem cell researchers at UCLA were able to grow functioning cardiac cells using mouse skin cells that had been reprogrammed into cells with the same unlimited properties as embryonic stem cells.

The finding is the first to show that induced pluripotent stem cells or iPS cells, which don’t involve the use of embryos or eggs, can be differentiated into the three types of cardiovascular cells needed to repair the heart and blood vessels.

The discovery could one day lead to clinical trials of new treatments for people who suffer heart attacks, have atherosclerosis or are in heart failure, said Dr. Robb MacLellan, a researcher at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research and senior author of the study. Researchers also were able to differentiate the iPS cells into several types of blood cells, which may one day aid in treating blood diseases and in bone marrow transplantation.

“I believe iPS cells address many of the shortcomings of human embryonic stem cells and are the future of regenerative medicine,” said MacLellan, an associate professor of cardiology and physiology. “I’m hoping that these scientific findings are the first step towards one day developing new therapies that I can offer my patients. There are still many limitations with using iPS cells in clinical studies that we must overcome, but there are scientists in labs across the country working to address these issues right now.”

The study, which brought together stem cell and cardiology researchers at UCLA, appears online May 1, 2008 in the journal Stem Cells. The article can be accessed at www.stemcells.com/papbyrecent.dtl.

Last June, UCLA stem cell researchers were among several scientific teams that were the first to reprogram mouse skin cells into cells resembling embryonic stem cells, which have the ability to become every cell type found in the body. MacLellan and his team used UCLA’s iPS cells in their study.

Although iPS cells are believed to be very similar to embryonic stem cells, further study needs to be done to confirm their differentiation potential. MacLellan’s study proved that iPS cells can be induced into becoming cardiovascular cells, an important step in the confirmation process.

“Theoretically, iPS cells are able to differentiate into 220 different cells types,” said Dr. Miodrag Stojkovic, co-editor of Stem Cells. “For the first time, scientists from UCLA were able to induce the differentiation of mouse iPS cells into functional heart cells.”

In MacLellan’s study, the iPS cells were cultured on a protein matrix known to direct embryonic stem cells into differentiating into cardiovascular progenitor cells, immature heart cells that can give rise to mature cardiac cells that perform different functions. The progenitor cells were then isolated from the other iPS cells that did not differentiate using a protein marker called KDR, a growth factor receptor expressed on the surface of the progenitor cells.

Once isolated, the cardiovascular progenitor cells were coaxed into becoming cardiomyoctyes, or mature heart muscle cells that control heartbeat, endothelial cells, which form rudimentary blood vessels, and vascular smooth muscle cells, the specialized cells that line blood vessel walls. Once mature, the cardiomyocytes beat in the Petri dish.

Studies are under way now at UCLA to determine if human iPS cells behave the same way as the mouse cells behave. If they do, the time may come when a person could use their own skin cells to create individualized iPS cell lines to provide cells for cardiac repair and regeneration, MacLellan said.

It is vital to be able to grow and isolate progenitor, or partially differentiated, cells that can create the three types of cardiac cells for potential clinical use. When embryonic stem cells are injected directly into the heart in animal models, they create tumors because the cells differentiate not only into cardiac cells but into other cells found in the human body as well. Likewise, using embryonic stem cells garnered from other sources than the patient could result in rejection of the injected cells.

The use of iPS cells may solve those problems. If the iPS cells come from the patient, rejection should not be an issue. Additionally, the use of cells that are already partially transformed into specific cardiac cell types may prevent tumor growth. The use of iPS cells also sidesteps the controversy some associate with deriving pluripotent stem cells from embryos or eggs, MacLellan said.

“Our hope is that, based on this work in mice, we can show that similar cardiovascular progenitor cells can be found in human iPS cells and, using a similar strategy, that we can isolate the progenitor cells and differentiate them into the cells types found in the human heart,” MacLellan said.

The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 150 members, the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The institute supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science