Scientists Look To Europe As Evolutionary Seat
Posted: Sunday, February 17, 2002
Source: University Of North Carolina School Of Medicine (http://www.med.unc.edu/)
CHAPEL HILL - New research in yeast cells may have pinpointed a key enzyme in the molecular circuitry that silences genes. The new enzyme, Set2, could prove critical for helping regulate gene expression in the ordered cycle of growth and division common to all living cells that have a nucleus. Thus, it may play an important role throughout life, beginning with early development, in gene regulation.
The research could also have consequences for the design of new targeted treatments for human diseases, including cancer, according to Dr. Brian D. Strahl, assistant professor of biochemistry and biophysics at the University of North Carolina at Chapel Hill School of Medicine. Strahl, the report's principal author, conducted the study while a postdoctoral researcher in the University of Virginia laboratory of senior co-author Dr. C. David Allis.
"The findings add to our knowledge of a basic and very important process and could offer new insight as to why certain genes in cancer are inappropriately expressed and how that might be corrected," Strahl said.
The new report is published in the March 2002 edition of the journal Molecular and Cellular Biology and on the journal's Web site (see below).
The process referred to by Strahl involves chromatin, a multifolded, ribbon-like complex of DNA wrapped around histone proteins. This class of proteins is one of the most highly conserved, appearing in all organisms having nucleated cells. While chromatin packaging allows for efficient storage of genetic information, it also impedes access to DNA by transcription factors, proteins that regulate gene expression.
Among the biochemical modification mechanisms that can dynamically change chromatin's structure - its loosening or tightening - is histone methylation. This modification mainly occurs on lysine residues, one of the amino acids that comprise the tail region of histone molecules.
Recent research at UNC and elsewhere has linked gene silencing, or deactivation, to methylation of particular lysines on the amino acid tail of the histone H3 molecule.
"The identity of any enzyme responsible for this modification was unknown until a few years ago when the first lysine 9-specific histone methyltransferase was identified," said Dr. Yi Zhang, a UNC biochemistry colleague of Strahl's. In December 2001, Zhang reported (in Molecular Cell) having identified the enzyme Set7, which modifies lysine 4 on histone H3 in mammalian cells. By methylating H3 at lysine 4, Set7 makes the chromatin structure more open, so other proteins can access the gene.
In the latest study, Strahl and co-authors described the identification and characterization of Set2, a novel histone methyltransferase that is site-specific for lysine 36 of the H3 tail. Set2 is responsible for methylation at this site. However, the researchers noted that in doing so "it helps to represses or silence gene transcription." Thus, according to Strahl, Set2 might be "a co-regulator of transcription" in the sense that it turns genes "off" instead of "on" as in the case of Set7.
"During development, you have different sets of genes that are important for, say, limb formation, and when the limbs are completed, the genes responsible for them must be turned off," Set2 may thus represent an "off switch" for gene regulation in cells.
In addition, Strahl said this modification could be part of an emerging 'molecular code' of histone modifications that ultimately regulate these processes.
"We believe that methylation and other modifications that affect histone proteins (acetylation, phosphorylation) are all dynamically involved and play critical roles in gene activation and deactivation at the appropriate times."
This process, he explains, possibly could work by the ability of these modifications to bring in additional proteins that result in opening or closing of the chromatin molecule. Further work might reveal the partners that interact with this enzyme, some of which may already be well studied, Strahl said. "Lysine 36 is much deeper into the histone tail than the other lysines that have captured so much recent attention. Although it's still not well understood, we now have some molecular insights into what this modification is doing."
This study was supported by grants from the National Institutes of Health.
Send page by E-Mail "Wishful Thinking" Gene Regulates Neural Development
Posted: Thursday, February 14, 2002
Source: Howard Hughes Medical Institute (http://www.hhmi.org/)
Two research teams have converged on a novel gene that appears to regulate key aspects of communication between nerve and muscle cells. Knowing the identity and function of these regulatory signals, which have remained largely mysterious until now, will allow researchers to better understand how the nervous system forges important connections during development.
The two research teams - one led by Howard Hughes Medical Institute investigator Michael O' Connor and his colleagues -- reported the discovery and characterization of the gene in fruit flies in articles in the February 15, 2002, issue of Neuron. The other team, led by former HHMI investigator Corey Goodman, discovered the same gene via a different route.
Both research teams identified the gene, wishful thinking (wit), by studying the larval neuromuscular junction (NMJ) in the fruit fly Drosophila. The Drosophila NMJ consists of 30 muscle fibers that are attached to 35 neurons. The well-characterized system is a prime model for exploring how muscle growth triggers the growth of its innervating motor neurons that drive muscle contraction.
One of the central features of this increase in neuronal growth is the parallel increase in the number of synapses -- the junctions between the neurons and muscle cells that trigger muscle contraction. Synaptic development also occurs in the brain and elsewhere within the nervous system in both invertebrates and vertebrates.
"It's been pretty clear from a number of experiments that there is some kind of signaling that happens at the neuromuscular junction that coordinates the muscle growth with synapse growth," said O'Connor, who is at the University of Minnesota. "Otherwise, the fly ends up with muscle cells that don't receive enough neurotransmitters to contract properly, or they receive too much and overcontract."
O'Connor and his colleagues were not specifically searching for genes involved in synaptic development when they began their screen of the Drosophila genome. Rather, they were looking for new members of the "bone morphogenetic protein" (BMP) receptor family. BMPs have previously been implicated in mediating many different aspects of development.
"Before we began the search, we didn't know that there was any BMP signaling in neurons," said O'Connor. "It has been known for some time that BMPs can affect neuronal cell fate, but that's very different from synaptic growth. So, we set out to identify genes for receptors, isolate mutants and just go where the resulting phenotypes took us."
Taking a different approach, Goodman and his colleagues at the University of California, Berkeley, did a direct screen for mutations in Drosophila genes that affect synaptic growth in Drosophila larvae. According to Goodman, synaptic growth likely involves proteins on either side of the synapse between neurons and muscle cells -- that is, the transmitting "presynaptic" side on the neuron and the receiving "postsynaptic" side on the muscle cell.
"From many experiments we had done over the past five years, we had accumulated evidence that the two sides of the synapse had a complex conversation with each other to regulate size and strength," said Goodman, who is now President and Chief Executive Officer at Renovis, Inc., a biotechnology company in San Francisco. "The genetic evidence clearly suggested the existence of several different retrograde factors -- signaling molecules that originated from the postsynaptic side of the synapse that influenced the growth or amount of transmitter release by the presynaptic side."
Researchers in Goodman's laboratory mounted a large-scale effort to create fly mutants that exhibited abnormalities in various parts of the synaptic machinery, which they detected using microscopic examination.
The two research teams found one BMP receptor gene -- which they dubbed wishful thinking -- that seemed to be involved in synaptic growth and development.
"The first hint that wit probably had a neuronal aspect to its function came when we looked at the expression pattern for the receptor and found it to be heavily expressed in the nervous system," said O'Connor. Other researchers had already screened the chromosomal region containing wit for mutations, and O'Connor and his colleagues identified fly mutations in which wit function was eliminated. Although the mutant flies died before they emerged from their pupal case, initial examination of those flies revealed no obvious abnormalities. At that point, the researchers believed it was only wishful thinking to hope for a more dramatic effect of the mutation -- hence the gene's name, said O'Connor. But when lead author of the Neuron paper, Guillermo Marques, studied the mutants more closely, he discovered something surprising.
"Guillermo saw that the flies were moving inside the pupal case, but they couldn't get out -- and if he pulled them out, they had very spastic movements. This suggested to us that they had a neuronal defect of some sort but the animals' nerve cells appeared normal," said O'Connor.
Two of O'Connor's co-authors, Bing Zhang and Hong Bao of the University of Texas, Austin, discovered that even though the general architecture of the mutant flies' nervous systems appeared normal, these animals exhibited severe defects in synaptic transmission. Their additional studies revealed that the mutants were also defective in releasing neurotransmitters from tiny sacs called synaptic vesicles. Examination of the synapses of the mutant flies' neurons also revealed that they had fewer synaptic "boutons" -- the small bulbs from which the neuron sends signals to the muscle cell.
O'Connor and his colleagues also began to trace how the receptors produced by the wit gene in motor neurons were receiving signals from muscle cells. They showed that signals sent to the motor neurons activated transcription factors, molecules that switch on genes involved in developing synapses.
O'Connor and his colleagues plan to trace how the signal sent from the muscle cell to the motor neuron moves down the axon to the main cell body of the neuron, where it triggers more signaling. Both O'Connor and Goodman are also examining how the Wit protein signal regulates synaptic growth.
"While until now there has been only circumstantial evidence that there is signaling between muscle cells and neurons that coordinate their formation, we didn't know what those molecules might be," said O'Connor. "So, this is the first signaling cascade that's been identified that must be involved in this coordination."
"This paper is just the beginning," said Goodman. "All of the ongoing work points to the discovery of a retrograde signaling mechanism, in which the postsynaptic side of the synapse sends a signal that is received by Wit and another receptor subunit on the presynaptic side, and this regulates synaptic growth." Goodman termed the discovery of the wit gene "a major breakthrough in the field" that would certainly lead to searches in vertebrates for similar genes that control synaptic size and strength.
Send page by E-Mail Study Associates Differences In Mood With Activity In A Specific Area Of The Brain
Posted: Thursday, February 14, 2002
Source: Vanderbilt University (http://www.vanderbilt.edu/)
Are you moody? If so, then there is a small area near the front of your brain - an inch or two behind your right eye (if you are right handed) - that is probably working overtime.
That is the conclusion of a new study, published Feb. 12 in the online Early Edition of the Proceedings of the National Academy of Sciences, which found a significant association between activity in a specific area of the brain and individual differences in mood.
"There are lots of beliefs about the relationship of individual differences in emotional behavior and brain function, but this is one of the first times we've seen direct evidence of an association with a specific brain region," says David H. Zald, assistant professor of psychology at Vanderbilt University, who co-authored the paper with Dorothy L. Mattson from the Minneapolis Veterans Affairs Medical Center and José V. Pardo from the University of Minnesota. The study used the brain imaging technique called positron emission tomography (PET) to record the levels of brain activity in two groups totaling 89 individuals. The subjects ranged in age from 18 to 55 years, with a median age in the mid-20s. There were slightly more men than women. None of the participants had a history of medical or neurological problems or were using mood-affecting medicines. They were all right-handed, because of potential differences in the brains of left- and right-handers.
Before the brain scans were taken, the individuals filled out a questionnaire that asked them a series of questions about the extent to which they had experienced unpleasant moods during the previous month. They then used these answers to rate each individual on a "negative affect" scale. Negative affect is a technical term that includes a range of unpleasant mood states, ranging from irritability to anxiety to anger. Previous studies have established the reliability of the negative-affect scale and have shown that individuals who rate high on the scale are at increased risk of developing depression or anxiety disorders.
After scanning the first group of 51 subjects, the researchers compared the levels of brain activity of all the subjects. They looked for areas where the activity level varied in accordance with patients' rating on the negative affect scale, showing either increasing or decreasing activity levels in those with higher negative-affect ratings.
"The most striking positive correlation we found was localized in only one small region of the brain, the ventromedial prefrontal cortex," says Zald. "Because this is just a correlation, we don't know whether this activity is the cause or the effect of negative mood states. Such a connection does make sense, however, because animal studies show that this region of the brain controls heart rate, breathing, stomach acidity levels, sweating and similar autonomous functions that have a close connection to mood." In order to double-check their findings, the researchers assembled a second group of 38 subjects. They put them through the same procedure and came up with essentially the same results: the variation of activity associated with differences on the negative affect scale account for about 20 percent of the total variation in the activity levels measured in the region.
Since the time of the ancient Greeks, there has been speculation that the brain is the basis of personality, but it is only within the last 20 years that scientists have developed instruments capable of measuring brain activity with enough accuracy to address this question directly. "With increased knowledge of the relationship between brain function and mood, we should be able to find more effective ways to treat the millions of Americans who suffer from clinical depression each year," says Zald.
Send page by E-Mail First View Of A Newborn Millisecond Pulsar?
Posted: Tuesday, February 12, 2002
Source: European Space Agency (http://www.esa.int)
Combining Hubble Space Telescope images with radio observations has revealed a highly unusual system consisting of a fast spinning pulsar and a bloated red companion star. The existence of the system is something of a mystery - the best explanation so far is that we have our first view of a millisecond pulsar just after it has been 'spun up' by its red companion star. Although more than 90 specimens of the exotic species of fast-spinning 'millisecond pulsars' are known today, no observations have yet been made to back up the theory of how they reached this state. A series of observations of the millisecond pulsar PSR J1740-5340 (spinning at 274 times per second) and its companion star from the ESA/NASA Hubble Space Telescope and the Parkes radio telescope seem to show the final stage of the pulsar acceleration process for the first time.
The generally favoured 'recycling scenario' describing the creation of millisecond pulsars proposes that an old, slowly rotating neutron star begins to absorb matter from its elderly companion star, typically a red giant. The matter hits the surface of the neutron star and transfers energy to make it rotate faster. The process ends when the pulsar has been revitalised and is rotating at hundreds of times per second (hence a millisecond pulsar), and its companion almost emptied of matter and turned into a white dwarf.
A team of scientists from Bologna Astronomical Observatory conducted a series of Hubble observations of the pulsar-companion system in the globular cluster NGC 6397. The observations show that the millisecond pulsar's companion is not the expected white dwarf, but a bloated red star, whose radius is about 100 times greater than that of a white dwarf and at least five times greater than a normal star of similar mass! This unique couple orbit around each other in 1.35 days.
The observations also indicate the abnormal presence of large amounts of gas in the system. This gas is released from the bloated companion star and soon will be swept away by the recently accelerated pulsar. Once the pulsar has been spun up it can no longer absorb gas from the companion.
Lead astronomer Francesco Ferraro explains: "We have certainly discovered a very unusual pair. A system consisting of a millisecond pulsar and a star that is not a white dwarf has never been seen before. Our favoured theory is that we are seeing the system before the bloated red star has been `emptied' of gas and turned into a white dwarf. If this compelling hypothesis is wrong then the companion star could be a normal star in the globular cluster that has been captured by the pulsar by chance. Maybe it has expelled the white dwarf that we normally find in such systems."
At last astronomers have observations to back the theory of millisecond pulsar births, and the discovery opens a new window on the evolution of millisecond pulsars.
Editor's Note: The original news release can be found at http://www.esa.int/export/esaCP/ESAU80VTYWC_index_0.html
Send page by E-Mail Evolutionary Body Change Demo Answers Creationists
Posted: Saturday, February 9, 2002
FIRST GENETIC EVIDENCE UNCOVERED OF HOW MAJOR CHANGES
IN BODY SHAPES OCCURRED DURING EARLY ANIMAL EVOLUTION
Biologists at the University of California, San Diego have uncovered the first genetic evidence that explains how large-scale alterations to body plans were accomplished during the early evolution of animals.
In an advance online publication February 6 by Nature of a paper scheduled to appear in Nature, the scientists show how mutations in regulatory genes that guide the embryonic development of crustaceans and fruit flies allowed aquatic crustacean-like arthropods, with limbs on every segment of their bodies, to evolve 400 million years ago into a radically different body plan: the terrestrial six-legged insects.
The achievement is a landmark in evolutionary biology, not only because it shows how new animal body plans could arise from a simple genetic mutation, but because it effectively answers a major criticism creationists had long leveled against evolution—the absence of a genetic mechanism that could permit animals to introduce radical new body designs.
"The problem for a long time has been over this issue of macroevolution," says William McGinnis, a professor in UCSD’s Division of Biology who headed the study. "How can evolution possibly introduce big changes into an animal’s body shape and still generate a living animal? Creationists have argued that any big jump would result in a dead animal that wouldn’t be able to perpetuate itself. And until now, no one’s been able to demonstrate how you could do that at the genetic level with specific instructions in the genome."
The UCSD team, which included Matthew Ronshaugen and Nadine McGinnis, showed in its experiments that this could be accomplished with relatively simple mutations in a class of regulatory genes, known as Hox, that act as master switches by turning on and off other genes during embryonic development. Using laboratory fruit flies and a crustacean known as Artemia, or brine shrimp, the scientists showed how modifications in the Hox gene Ubx—which suppresses 100 percent of the limb development in the thoracic region of fruit flies, while its crustacean counterpart from Artemia only represses 15%—would have allowed the crustacean-like ancestors of Artemia, with limbs on every segment, to lose their hind legs and diverge 400 million years ago into the six-legged insects.
"This kind of gene is one that turns on and off lots of other genes in order to make complex structures," says Ronshaugen, a graduate student working in William McGinnis’ laboratory and the first author of the paper. "What we’ve done is to show that this change alters the way it turns on and off other genes. That’s due to the change in the way the protein produced by this gene functions."
"The change in the mutated protein allows it to turn off other genes," says William McGinnis, who discovered with two other scientists in 1983 that the same Hox genes in fruit flies that control the placement of the head, thorax and abdomen during development are a generalized feature of all animals, including humans. "Before the evolution of insects, the Ubx protein didn't turn off genes required for leg formation. And during the early evolution of insects, this gene and the protein it encoded changed so that they now turned off those genes required to make legs, essentially removing those legs from what would be the abdomen in insects."
The UCSD team’s demonstration of how a mutation in the Ubx gene and changes in the corresponding Ubx protein can lead to such a major change in body design undercuts a primary argument creationists have used against the theory of evolution in debates and biology textbooks. Their specific objection to the idea of macroevolutionary change in animals is summed up in a disclaimer that the Oklahoma State Textbook Committee voted in November, 1999 to include in that state’s biology textbooks:
"The word evolution may refer to many types of change. Evolution describes changes that occur within a species. (White moths, for example, may evolve into gray moths). This process is microevolution, which can be observed and described as fact. Evolution may also refer to the change of one living thing into another, such as reptiles and birds. This process, called macroevolution, has never been observed and should be considered a theory."
"The creationists’ argument rests in part on the fact that animals have two sets of chromosomes and that in order to get big changes, you’d need to mutate the same genes in both sets of chromosomes," explains McGinnis. "It’s incredibly unlikely that you would get mutations in the same gene in two chromosomes in a single organism. But in our particular case, the kind of mutation that’s in this gene is a so-called dominant mutation, so you only need to mutate one of the chromosomes to get a big change in body plan."
The discovery of this general mechanism for producing major leaps in evolutionary change has other implications for scientists. It may provide biologists with insights into the roles of other regulatory genes involved in more evolutionarily recent changes in body designs. In addition, the discovery in the UCSD study, which was financed by the National Institute of Child Health and Human Development, of how this particular Hox gene regulates limb development also may have an application in improving the understanding human disease and genetic deformities.
"If you compare this gene to many other related genes, you can see that they share certain regions in their sequences, which suggests that their function might be regulated like this gene," says Ronshaugen. "This may establish how, not only this gene, but relatives of this gene in many, many different organisms actually work. A lot of these genes are involved in the development of cancers and many different genetic abnormalities, such as syndactyly and polydactyly, and they may explain how some of these conditions came to be."
Graphic and image of Artemia, along with original news release. Credit: Matthew Ronshaugen, UCSD.
[Contact: William McGinnis, Matthew Ronshaugen, Kim McDonald]
Send page by E-Mail Researchers find new photoreceptor and visual system in the eye
Posted: Wednesday, February 6, 2002
PROVIDENCE, R.I. — Brown University researchers have found a new cell in the eye that acts as a photoreceptor – like a rod or cone – and sets the body’s circadian clock.
For nearly 150 years, scientists considered rods and cones to be the eye’s only photoreceptors – cells that turn light energy into electrical impulses. Many cells in the eye and brain respond to light but only because they are linked to the rods and cones by complex pathways. These cells are responsible for the nervous system’s sensitivity to patterns, objects and movement in the visual world.
Now there is a third photoreceptor, say scientists at Brown. The new cell resides deeper in the retina than rods and cones and looks remarkably different, more like the underside of a canopy of twisted tree branches.
The scientists dub the new cell “an intrinsically photosensitive ganglion cell.” It also turns light energy directly into brain signals. These signals govern the body’s 24-hour clock, they say, adding that this retinal input is what helps people get over jet lag.
In the February 8 issue of Science, the researchers describe the new cells, discovered in the retinas of rats, and their direct pipeline to the brain. The cells send out nerve fibers which travel within the optic nerve and connect with the clock region in the brain.
“We think this population of cells plays a role in setting the circadian clock and probably in a variety of other functions where all the brain needs to know is how bright it is,” said lead author David Berson, associate professor of neuroscience. “It is a visual system that runs parallel to the one we have been thinking about all these years. Now we have to rethink how the retina works and how the brain understands what is going on in the visual world. This is a new kind of representation of light by the nervous system, a new way for the brain to react to the visual environment.”
The scientists went looking for the cells in an effort to explain why some people who are functionally blind – whose rods and cones do not work – can still adjust their biological rhythms to match the day and night of the external world.
“There is a strong likelihood that there are identical cells in humans,” Berson said. “This could explain why certain people who are functionally blind due to retinal degeneration continue to set their biological clock according to the day/night cycle. These people have suffered damage to photoreceptors and to a visual system we knew about. What we didn’t know until now was what sort of photoreceptor system still operated.”
In experiments, the researchers injected a fluorescent dye into the tiny part of a rat’s brain that governs the 24-hour clock cycle. The dye traveled back to the new photoreceptors in the eye. The researchers then found the dye-filled cells, recorded their electrical activity, and found that they continued responding to light whether or not they were connected to the retina or brain.
“We concluded that a response to light was intrinsic to these cells,” Berson said. Although scientists have long known that ganglion cells – the output cells of the retina – play a key role in vision, they were not considered to have any photoreceptors among them.
A photoreceptor is a cell in the eye that contains a chemical called a photopigment that changes its properties in response to light. This change triggers a cascade of biochemical reactions and an electrical response in the photoreceptor. This signal then moves along a pathway between the cells and the brain.
The paper’s coauthors include undergraduate Felice Dunn and postdoctoral researcher Motoharu Takao. The National Eye Institute funded the research.
Berson and Takao are two of the co-authors of another paper in the February 8 issue of Science that points to the chemical melanopsin as the likely photopigment in these cells and traces their pathways to the brain. The other authors of that paper are from the Howard Hughes Medical Institute and Johns Hopkins University School of Medicine.
The newly discovered retinal photoreceptor, right, is an intrinsically photosensitive ganglion cell. The transduction of light into electrical signals appears to take place throughout the cell body (the dark, dyed circular structure) as well as in its slender, tangled dentrites.
In this recording, the cell’s electrical activity has been transformed so the human ear can hear it. As the recording begins, the cell sits in the dark, awaiting a stimulus. About 10 seconds into the recording, a tone sounds, marking the moment when a bright light is turned on and kept on. For several seconds, there is no detectable response from the cell, but eventually it begins to fire nerve impulses, heard as popping sounds. The delay between the onset of stimulus and the beginning of the response is extraordinarily long compared with conventional photoreceptors (rods and cones). This is presumably because the newly discovered photoreceptors are specialized to detect slow changes in environmental lighting, not the rapid events that are so important in pattern vision. With constant light stimulation, the rate of firing gradually increases and then plateaus at a rate that encodes the intensity of the light flooding the cell.
[See also statement by sleep researcher Mary Carskadon.]
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