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January 2004

New Study Shows Neanderthals Were Not Our Ancestors
Posted: Tuesday, January 27, 2004
Source: New York University

In the most recent and mathematically rigorous study to date determining whether Neanderthals contributed to the evolution of modern humans, a team of anthropologists examining the skulls of modern humans and Neanderthals as well as 11 existing species of non-human primates found strong evidence that Neanderthals differ so greatly from Homo sapiens as to constitute a different species.

The findings could potentially put to rest the decades-long debate between proponents of the regional continuity model of human origins, which maintains that Neanderthals are a subspecies of Homo sapiens which contributed significantly to the evolution of modern Europeans, and the single-origin model, which views Neanderthals as a separate, distinct species. The research will be published in the Proceedings of the National Academy of Sciences.

The scientists, led by Katerina Harvati of New York University, used a new technique known as geometric morphometrics to measure the degree of variation between and amongst living primate species, represented by over 1000 specimens. The scientists measured 15 standard craniofacial landmarks on each of the skulls and used 3-D analysis to superimpose each one in order to measure their shape differences, irrespective of size. Random samples were chosen from each species and the differences between them were calculated 10,000 times, in order to simulate the sampling effects of the fossil record. . The data used included Neanderthal fossils , Upper Paleolithic European modern human fossils, and recent human populations, as well as data from living African apes and Old World Monkeys.

"Our motivation was to devise a quantitative method to determine what degree of difference justified classifying specimens as different species," said Harvati. "The only way we could effectively do this was to examine the skeletal morphology of living species today and come up with models. From these data, we were able to determine how much variation living primate species generally accommodate, as well as measure how different two primate species that are closely related can be."

The study found that the differences measured between modern humans and Neanderthals were significantly greater than those found between subspecies or populations of the other species studied. The data also showed that the difference between Neanderthals and modern humans was as great or greater than that found between closely related primate species.

Among the species of existing primates included in the study were gorillas and chimpanzees, which are known to be the closest relatives to humans, as well as mandrills, macaques and baboons, who represent a greater degree of geographic and ecological diversity. As a result, Harvati's team's study constitutes the most extensive inter- and intra-species comparison of primate evolution ever recorded.

"What the data give us is a robust analysis of a widely representative sample of primates, and provides the most concrete evidence to date that Neanderthals are indeed a separate species within the genus Homo," Harvati added.


The PNAS paper, entitled "Neanderthal taxonomy reconsidered: Implications of 3D primate models of intra- and interspecific differences," was co-authored by Stephen R. Frost of New York College of Osteopathic Medicine at the New York Institute of Technology and Kieran P. McNulty of Baylor University, and will be available on their website the week of January 26-30, 2004.

Katerina Harvati is an assistant professor of anthropology at New York University, specializing in human evolution, Neanderthals and modern human origins. She conducts fieldwork in her native Greece. She earned a bachelors degree from Columbia University and a Ph.D. from the City University of New York Graduate Center. The studies were funded by grants from the National Science Foundation, L. S. B. Leakey, Wenner-Gren and Onassis Founadion, the American Museum of Natural History, the Smithsonian Institution and the New York Consortium in Evolutionary Primatology.

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Researchers Show Evolutionary Theory Adds Up
Posted: Friday, January 16, 2004
Source: University Of Alberta

All living plants and animals are likely derived from two primitive species of bacteria, a mathematics professor at the University of Alberta has shown.

Dr. Peter Antonelli and a former post-doctoral student of his, Dr. Solange Rutz, used an original mathematical modeling system and software program to evaluate and compare the two main theories of biological evolution.

One theory, put forward by Dr. Lynn Margulis of the University of Massachusetts, proposes that a "mother" bacteria (Bdellavibrio) and a "father" bacteria (Thermoplasma acidophilum) "exchanged energy" in a stable, dependable, and consistent way about 3.2 billion years ago to form all subsequent multicellular organisms, Antonelli explained.

Another theory, put forward by Dr. Carl Woese of the University of Illinois, proposes multicellular organisms developed from many different bacteria interacting in many different ways 3.2 billion years ago.

Antonelli and Rutz's research showed that Woese's theory does not account for stability in the chemical exchange processes of many bacteria interacting, whereas Margulis's theory holds up under the scrutiny of Antonelli's modeling system. The study is published in the latest edition of Nonlinear Analysis: Real World Applications.

"We showed that the chemical production necessary to support Woese's theory is not dependable and not conducive to the formation of multicellular organisms, but Margulis's theory proves to be reliable," Antonelli said.

Antonelli decided to test the two theories after reading an article on the subject in the New York Times about three years ago. "I try to solve scientific problems with mathematics, and when I read this article, I thought, 'Hey, this is a problem I can solve.'"

Antonelli has also solved other problems with the 'Volterra-Hamilton' mathematical model that he developed. He has solved the mystery of succession in the crown of thorns population of the Great Barrier Reef. He is now working to define the succession of the Amazon Rain Forest to its current climax state. He is also seeking a unified theory of ecological evolution, and he feels he can achieve this in the not too distant future.

"I haven't always been trying to develop a unified theory, but as we have been putting pieces together, study by study, I can see now that's it's possible," said Antonelli, who has mentored more than 35 post-doctoral students and sits as an editor for eight journals.

Antonelli uses differential equations to explain social interactions and biological behaviours, and he laments that more biologists aren't attuned to this type of research.

"What we do is new and not a lot of people understand it yet," he said. "I've published in biology journals before, but most biologists don't read these articles because of the mathematics involved. We've got to convince [biologists] that it's worth the effort to learn the mathematics."

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Ancient DNA Mutations Permitted Humans To Adapt To Colder Climates
Posted: Friday, January 16, 2004
Source: University Of California - Irvine

Irvine, Calif., Jan. 12, 2004 -- How did early humans who migrated from Africa survive in the colder climates of Europe, Asia and the New World? According to a new UC Irvine study, it may be the same reason some people today are more prone

In the Jan. 9, 2004, issue of Science, a UCI research team reports that key mutations in the mitochondrial DNA (mtDNA) of human cells may have helped our migrating ancestors adapt to more northerly climates, and ultimately link people with this ancestral history to specific diseases.

Found outside the cell's nucleus, mitochondria are the power plants of cells that are responsible for burning the calories in our diet.

The cellular energy is used for two purposes: to generate heat to maintain our body temperature and to synthesize ATP (adenosine triphosphate), a chemical form of energy that permits us to do work such as exercise, think, write, and make and repair cells and tissues. The mtDNAs are the blue prints for our mitochondrial power plants and determine the proportion of the calories in our diet that are allocated to generate body heat versus work.

According to Douglas C. Wallace, the Donald Bren Professor of Biological Sciences and Molecular Medicine at UCI and one of the co-authors of the report, after early humans migrated to colder climates, their chances of survival increased when mutations in their mtDNA resulted in greater body heat production during the extreme cold of the northern winters.

"In the warm tropical and subtropical environments of Africa it was most optimal for more of the dietary calories to be allocated to ATP to do work and less to heat, thus permitting individuals to run longer, faster and to function better in hot climates," Wallace said. "In Eurasia and Siberia, however, such an allocation would have resulted in more people being killed by the cold of winter. The mtDNA mutations made it possible for individuals to survive the winter, reproduce and colonize the higher latitudes.

"This explains the striking correlation between mtDNA lineage and geographic location that we still see today in indigenous populations around the world."

It also explains why people with a certain ancestral history may be more susceptible to some diseases.

"When heat and cold are managed by technology, not metabolism, and people from warmer climates are eating the high fat and calorie diets of northern climates, there is a rise in obesity and the age-related degenerative diseases," Wallace said. "The caloric intake and local climate of many individuals are out of balance with their genetic history. Thus, our genetic history is linked to our current diseases, resulting in the new field of evolutionary medicine."

One link would be the production of oxygen radicals in cells. Created when mitochondria burn our dietary fuel, this by-product can be responsible for damaging and killing cells, leading to several age-related diseases. "When calories are unutilized for producing heat or ATP, they are redirected to generate oxygen radicals," Wallace said. "Since the mutated DNA of cold-adapted people allocates more calories to heat, there are fewer left over to generate oxygen radicals. Hence these people are less prone to aging and age-related degenerative diseases." (For more details on oxygen radicals, see below.)

In the study, Wallace and his UCI colleagues Eduardo Ruiz-Pesini, Dan Mishmar, Martin Brandon and Vincent Procaccio analyzed 1,125 human mtDNA sequences from around the world to reconstruct the mutational history of the human mtDNA back to the original mtDNA, known as the mitochondrial Eve.

Wallace is the director of the Center for Molecular and Mitochondrial Medicine and Genetics at UCI and is a faculty member in the Departments of Ecology and Evolutionary Biology, Biological Chemistry and Pediatrics. This study was funded by the National Institutes of Health and the Ellison Medical Foundation.

How mtDNA control the production of oxygen radicals

When mitochondria burn our dietary fuel, they generate a toxic by-product called oxygen radicals, the mitochondrial equivalent to the smoke generated by coal-burning power plants. Oxygen radicals damage the mitochondria, mtDNA and the surrounding cell. Eventually oxygen radicals can cause the cell to die when sufficient oxidative damage accumulates in the mitochondria and the cell.

Since many of the tissues of our bodies have a finite number of cells, when sufficient cells die organs malfunction, resulting in the symptoms of age-related degenerative diseases and aging. As a result, the chronic level of mitochondrial oxidative stress will determine an individual's aging rate and susceptibility to a variety of diseases such as diabetes, memory loss, forms of deafness and vision loss, cardiovascular disease, etc.

If all the calories that an individual consumes are used in generating carbon dioxide, water and energy, little fuel is left over to generate the oxygen radicals; however, if more calories are consumed than are needed to make energy, then these excess calories are stored as fat and drive a chronic increase in mitochondrial oxygen radical production.

Consider two individuals that eat the same number of calories and get the same amount of exercise. The individual with a mtDNA mutant that increases heat production will require more calories for energy production and thus will have fewer calories left over to produce oxygen radicals. This individual will be partially protected from age-related diseases and will live longer. By contrast, the individual with mitochondria that make more ATP per calorie burned will store fat and generate more oxygen radicals if he or she eats the same level of calories as the individual with the cold-adapted mitochondria.

About the University of California, Irvine: The University of California, Irvine is a top-ranked public university dedicated to research, scholarship and community. Founded in 1965, UCI is among the fastest-growing University of California campuses, with more than 23,000 undergraduate and graduate students and about 1,300 faculty members. The third-largest employer in dynamic Orange County, UCI contributes an annual economic impact of $3 billion.

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Gene may be key to evolution of larger human brain
Posted: Tuesday, January 13, 2004
Source: Howard Hughes Medical Institute

Howard Hughes Medical Institute researchers have identified a gene that appears to have played a role in the expansion of the human brain's cerebral cortex -- a hallmark of the evolution of humans from other primates.

By comparing the gene's sequence in a range of primates, including humans, as well as non-primate mammals, the scientists found evidence that the pressure of natural selection accelerated changes in the gene, particularly in the primate lineage leading to humans.

The researchers, led by Howard Hughes Medical Institute (HHMI) investigator Bruce Lahn at the University of Chicago, reported their findings in an advance access article published on January 13, 2004, in the journal Human Molecular Genetics. Patrick Evans and Jeffrey Anderson in Lahn's laboratory were joint lead authors of the article.

"People have studied the evolution of the brain for a long time, but they have traditionally focused on the comparative anatomy and physiology of brain evolution," said Lahn. "I would venture, however, that there really hasn't been any convincing evidence until now of any gene whose changes might have contributed to the evolution of the brain."

In this study, the researchers focused on a gene called the Abnormal Spindle-Like Microcephaly Associated (ASPM) gene. Loss of function of the ASPM gene is linked to human microcephaly a severe reduction in the size of the cerebral cortex, the part of the brain responsible for planning, abstract reasoning and other higher brain function. The discovery of this association by HHMI investigator Christopher A. Walsh and colleagues at Beth Israel Deaconess Medical Center is what prompted Lahn to launch an evolutionary study of the gene.

Lahn and his colleagues compared the sequence of the human ASPM gene to that from six other primate species shown genetically to represent key positions in the evolutionary hierarchy leading to Homo sapiens. Those species were chimpanzee, gorilla, orangutan, gibbon, macaque and owl monkey.

"We chose these species because they were progressively more closely related to humans," said Lahn. "For example, the closest relatives to humans are chimpanzees, the next closest are gorillas, and the rest go down the ladder to the most primitive."

For each species, the researchers identified changes in the ASPM gene that altered the structure of the resulting protein, as well as those that did not affect protein structure. Only those genetic changes that alter protein structure are likely to be subject to evolutionary pressure, Lahn said. Changes in the gene that do not alter the protein indicate the overall mutation rate the background of random mutations from which evolutionary changes arise. Thus, the ratio of the two types of changes gives a measure of the evolution of the gene under the pressure of natural selection.

Lahn and his colleagues found that the ASPM gene showed clear evidence of changes accelerated by evolutionary pressure in the lineage leading to humans, and the acceleration is most prominent in recent human evolution after humans parted way from chimpanzees.

"In our work, we have looked at evolution of a large number of genes, and in the vast number of cases, we see only weak signatures of adaptive changes," said Lahn. "So, I was quite surprised to see that this one gene shows such strong and unambiguous signatures of adaptive evolution -- more so than most other genes we've studied."

By contrast, the researchers' analyses of the ASPM gene in the more primitive monkeys and in cows, sheep, cats, dogs, mice and rats, showed no accelerated evolutionary change. "The fact that we see this accelerated evolution of ASPM specifically in the primate lineage leading to humans, and not in these other mammals, makes a good case that the human lineage is special," said Lahn.

According to Lahn, among the next steps in his research will be to understand how ASPM functions in the brain. Studies by Walsh and others hint that the protein produced by the gene might regulate the number of neurons produced by cell division in the cerebral cortex. Lahn and his colleagues plan functional comparisons of the ASPM protein among different species, to understand how this gene's function or regulation changes with evolution.

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Gene Essential For Development Of Normal Brain Connections
Posted: Friday, January 9, 2004
Source: University Of California - San Diego

Gene Essential For Development Of Normal Brain Connections Resulting From Sensory Input Discovered

Biologists at the University of California, San Diego and the Johns Hopkins University have discovered a gene that plays a key role in initiating changes in the brain in response to sensory experience, a finding that may provide insight into certain types of learning disorders.

After birth, learning and experience change the architecture of the brain dramatically. The structure of individual neurons, or nerve cells, changes during learning to accommodate new connections between neurons. Neuroscientists believe these structural changes are initiated when neurons are activated, causing calcium ions to flow into cells and alter the activity of genes.

In a paper featured on the cover of the January 9th issue of the journal Science, biologists at UCSD and the Johns Hopkins University medical school report the discovery of the first gene, CREST, known to mediate these changes in the structure of neurons in response to calcium.

"We discovered the gene CREST using a new method we developed to identify genes that are switched on in the presence of calcium," says Anirvan Ghosh, a professor of biology at UCSD who headed the study. "The brains of mice lacking CREST appear normal at birth, but do not develop normally in response to sensory experience after birth. This parallels some learning disorders in humans where the child appears normal initially, but by the age of two or three years it becomes clear that there are failures in the acquisition of new knowledge."

Neurons from normal mice develop a highly branched tree-like structure. In fact, much of the growth of the brain that occurs soon after birth is the development and branching of dendrites-the part of a nerve cell that receives input from other neurons. Thus, this branching allows neurons to form many different synapses, or connections, with many other neurons, permitting much cross talk between them. Neurons taken from mice lacking the CREST gene are more linear, like a plant shoot.

In addition, when individual neurons kept alive in a Petri dish are stimulated with calcium ions, they respond by developing highly branched dendrites, but neurons taken from mice lacking CREST fail to branch in response to calcium.

"CREST is the first example of a transcription factor-a protein that turns genes on and off-that appears to be specifically required for the development of brain neurons after birth," explains Ghosh, who conducted the study at his former laboratory at Johns Hopkins

His new laboratory at UCSD is currently working to determine what gene is targeted by CREST. Ghosh suspects the CREST gene might be turning on the production of chemicals called growth factors, for the stimulatory effect they have on cell development.

The CREST protein produced by that gene is made in several regions of the brain immediately after birth. In adults, the protein is produced in a region of the brain known as the hippocampus, which plays an important role in learning and memory. Because of this, Ghosh suspects that CREST may be necessary for the storage of new memories and the ability to learn. His laboratory is currently developing mice in which CREST expression is normal throughout most of development, so the brain develops normally, but then shuts off in the hippocampus when the mice reach adulthood. In this way, the researchers can test the specific role of CREST in learning and memory in adults.

"Humans also have CREST, and the CREST gene sequence is highly similar between mice and humans," says Ghosh. "If it turns out that CREST plays a role in learning and memory in the mouse, then it is very likely it also plays a similar role in humans."

The other researchers involved in the study are Hiroyuki Aizawa, Shu-Ching Hu, Kathryn Bobb, Karthik Balakriashnan, Inga Gurevich and Mitra Cowan. The study was supported by the National Institutes of Health, the March of Dimes Birth Defects Foundation, the Klingenstein Foundation, Merck and the Uehara Memorial Foundation.

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Biggest, Brightest Star Yet Observed
Posted: Tuesday, January 6, 2004
Source: University Of Florida

Star May Be Biggest, Brightest Yet Observed, Astronomers Say

GAINESVILLE, Fla. --- A University of Florida-led team of astronomers may have discovered the brightest star yet observed in the universe, a fiery behemoth that could be as much as much as seven times brighter than the current record holder. But don't expect to find the star which is at least 5 million times brighter than the sun in the night sky. Dust particles between Earth and the star block out all of its visible light. Whereas the sun is located only 8.3 light minutes from Earth, the bright star is 45,000 light years away, on the other side of the galaxy. It is detectable only with instruments that measure infrared light, which has longer wavelengths that can better penetrate the dust.

In a National Science Foundation-funded study scheduled to be presented today at the American Astronomical Society national conference in Atlanta, the team says the star is at least as bright as the Pistol Star, the current record holder, so named for the pistol-shaped nebula surrounding it. Whereas the Pistol Star is between 5 million and 6 million times as bright as the sun, however, the new contender, LBV 1806-20, could be as much as 40 million times the sun's brightness.

"We think we've found what may be the most massive and most luminous star ever discovered," said Steve Eikenberry, a UF professor of astronomy and the lead author of a paper on the discovery that was recently submitted to the Astrophysical Journal.

Eikenberry will discuss his findings in a news conference to be held by the society at 12:30 p.m. today at the Courtland Room in the Hyatt Regency Atlanta, where the conference is being held.

One longstanding problem with gauging the brightness of stars at great distances is that what seems at first to be one amazingly bright star turns out on closer examination to be a cluster of nearby stars. Don Figer, an astronomer at the Baltimore-based Space Telescope Science Institute who led the team that discovered the Pistol Star in 1997, said the high-quality data collected by the UF-led team reduced but did not eliminate this possibility.

"The high-resolution data prove that the object is not simply a cluster of lower mass stars, although it is possible that it is a collection of a few stars in a tight orbit around each other," Figer said. "More study will be needed to determine the distance and singularity of the object in order to establish whether the object is truly the most massive star known."

Astronomers have known about LBV 1806-20 since the 1990s. At that time, it was identified as a "luminous blue variable star" a relatively rare, massive and short-lived star. Such stars get their names from their propensity to display light and color variability in the infrared spectrum. Luminous blue variable stars are extremely large, with LBV 1806-20 probably at least 150 times larger than the sun, Eikenberry said. The stars are also extremely young by stellar time. LBV 1806-20 is estimated at less than 2 million years old. The sun in our solar system, by contrast, is 5 billion years old. Typical stars, such as the sun, live 10 billion years.

LBVs have "short and troubled lives," as Eikenberry put it, because "the more mass you have, the more nuclear fuel you have, the faster you burn it up. They start blowing themselves to bits."

Eikenberry's team made several key advances that led to the estimate of the star's oversized mass and brightness, he said.

One, they sharpened infrared images obtained from the Palomar 200-inch telescope at the California Institute of Technology's Palomar Observatory using a camera equipped with "speckle imaging," a relatively new technology for improving resolution of objects at great distances. "The shimmering that you see coming off a hot blacktop road in the summer the upper atmosphere kind of does that with star light," Eikenberry said. "Speckle imaging kind of freezes that motion out."

Composed of 17 astronomers and graduate students, the team also came up with an accurate estimate for the distance from the Earth to the bright star. Team members further determined its temperature, and how much of the star's infrared light gets absorbed by dust particles as the light makes its way toward Earth. The scientists relied on data collected by the Blanco 4-meter telescope at the National Optical Astronomy Observatory's Cerro Tololo Inter-American Observatory in Chile.

Each of these variables contributed to the estimate of the star's remarkable candlepower. "You correct for dust absorption, then you correct for temperature of the star, you correct for distance of the star all of those things feed into luminosity," Eikenberry said.

One of the mysteries about LBV 1806-20 is how it got so big. Current theories of star formation suggest they should be limited to about 120 solar masses, or 120 times as large as the sun, because the heat and pressure from such big stars' cores force matter away from their surfaces. Eikenberry said one possibility is that the big star was formed through shock-induced star formation, which occurs when a supernova blows up and slams the gaseous material in a molecular cloud into a massive star.

The star's size is not its only distinguishing characteristic. It is located in a small cluster of highly unusual or extremely rare stars, including a so-called "soft gamma ray repeater," a freakishly magnetic neutron star that is one of only four identified in the entire galaxy of 100 billion stars. With a magnetic field hundreds of trillions of times more powerful than Earth's magnetic field, this type of star gets its name from its periodic bursts of gamma rays. The cluster also apparently includes an infant or newly formed star. "We've got this zoo of freak stars, all crammed together really nearby, and they're all part of the same cluster of stars," Eikenberry said. "It's really kind of weird."

The original news release can be found here.

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'New World' link to Arctic find
Posted: Friday, January 2, 2004
By Paul Rincon
BBC News Online science staff

Humans occupied the freezing lands high above the Arctic Circle during the last Ice Age, say Russian archaeologists.

New Stone Age artefacts from Yana in northern Siberia have pushed back the human presence in the Arctic by around 16,000 years, surprising many experts.

The finds also hint that North America may have been populated much earlier than thought given the dig's relative proximity to the Bering Strait. Full Article

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Young Nerve Cells Can Rewind Their Developmental Clocks
Posted: Friday, January 2, 2004
Source: New York University Medical Center And School Of Medicine

A Big Surprise: Young Nerve Cells Can Rewind Their Developmental Clocks

Scientists have identified a gene in the cerebral cortex that apparently controls the developmental clock of embryonic nerve cells, a finding that could open another door to tissue replacement therapy in the central nervous system. In a new study, the researchers found that they could rewind the clock in young cortical cells in mice by eliminating a gene called Foxg1. The finding could potentially form the basis of a new method to push progenitor cells in the brain to generate a far wider array of tissue than is now possible.

The study, led by researchers at NYU School of Medicine, is published in the January 2, 2004 issue of Science magazine.

"What we found was a complete surprise," says Gordon Fishell, Ph.D., Associate Professor in the Department of Cell Biology at New York University School of Medicine. "No one had believed that it was possible to push back the birth date of a cortical neuron. There is this central tenet governing the process of brain development, which says that late progenitor cells [forerunners of mature cell types] cannot give rise to cell types produced earlier in development," he explains.

"Consequently, while some populations of stem cells exist in the adult brain, these cells are restricted to producing only a subset of cell types," notes Dr. Fishell. "If one's goal is to produce cells for replacement therapy, some method must be found to turn back the clock and allow adult stem cells to give rise to the wide variety of cells made during normal brain development."

Eseng Lai, Ph.D., of Merck & Co. and one of the study's co-authors, cloned the Foxg1 gene while he was working at Memorial Sloan-Kettering Cancer Center in New York. He also did seminal work in the late 1990s showing that when the gene is eliminated in embryonic mice, the brain's cerebral hemispheres barely develop. Subsequent work demonstrated that the gene played a role in the early phases of cortical development.

The cerebral cortex is massively folded gray matter incorporating billions of neurons. Despite its complexity, the cortex comprises six orderly layers of cortical cells that are laid down during development at a precise time and in a precise sequence. In the study, the researchers asked which cortical cell types embryonic mice lacking Foxg1 can generate. Carina Hanashima, Ph.D., a postdoctoral fellow in Dr. Fishell's laboratory who had previously worked with Dr. Lai, conducted a series of experiments that made the analysis possible.

The progenitor cells for the cortex are born in a zone deep in the brain, and migrate to their assigned layer, depending on the time they are born. So a cortical cell's identity is based on the date of its birth. The first cortical cells to be born populate layer 1, the most superficial layer, which is made up of special Cajal-Retzius (CR) cells. The next cells born migrate to the innermost layer, layer 6. Subsequent layers pile up above layer 6 (between layers 6 and 1), and in descending numerical order from 5 to 2. Each layer has a specific type of neuron associated with it.

The researchers looked at the cortical layers in embryonic mice at a time in their development when layers 1, 6, and 5, would normally have already been formed. In mice lacking the Foxg1 gene, the researchers found that only layer 1, which is made up of CR cells, was present, and these cells were abundant. The absence of other cell types implicated the gene in producing later-born cortical cell types.

One of the ways the scientists were able to identify CR cells was by the expression of a protein called reelin, which plays a vital role in building the developing brain and is only present in CR cells. Mice lacking the protein stumble around so much that they were named "reelers." The cortical layers in these mice are scrambled. In recent years, reelin deficiencies have been linked to such human disorders as schizophrenia and epilepsy.

In subsequent experiments, the researchers asked how the overproduction of CR cells occurs. They used a clever biochemical manipulation that served as a kind of genetic stop watch, allowing them to temporarily turn off the Foxg1 gene in late progenitor cells, after the normal birth date of CR cells had passed. In this way, they observed that cortical cells destined to become layer 5 became CR cells instead. Apparently, the gene orchestrates the program responsible for ensuring that the cortical layers of the cerebral cortex are laid down in a precise sequence. When the gene is inactivated or turned off, the program seems to revert to its earliest stage.

The researchers do not know how late in the game they can play their genetic tricks. If they turn off the Foxg1 gene at a later time in development, such as when cortical layers 2 or 3 are forming, will progenitor neuronal cells still become CR cells? Are there other genes that control the developmental clock? If such genes exist, it may be possible to turn these genes off in adult neural stem cells, and thereby generate a far broader array of tissue than otherwise possible. "I would say that the chances of this happening are very remote," says Dr. Fishell, "but then again, I never thought that the clock could have been turned back in neuronal progenitor cells."

The authors of the study are Gordon Fishell and Carina Hanashima of NYU School of Medicine; Eseng Lai of Merck; Suzanne Li of Memorial Sloan-Kettering Cancer Center; and Lijian Shen of Weill Medical College of Cornell University.

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