Which Came First, the Head or the Brain?

The sea anemone, a cnidarian, has no brain. It does have a nervous system, and its body has a clear axis, with a mouth on one side and a basal disk on the other. However, there is no organized collection of neurons comparable to the kind of brain found in bilaterians, animals that have both a bilateral symmetry and a top and bottom. (Most animals except sponges, cnidarians, and a few other phyla are bilaterians.) So an interesting evolutionary question is, which came first, the head or the brain? Do animals such as sea anemones, which lack a brain, have something akin to a head?

In this issue of PLOS Biology, Chiara Sinigaglia and colleagues report that at least some developmental pathways seen in cnidarians share a common lineage with head and brain development in bilaterians. It might seem intuitive to expect to find genes involved in brain development around the mouth of the anemone, and previous work has suggested that the oral region in cnidarians corresponds to the head region of bilaterians. However, there has been debate over whether the oral or aboral pole of cnidarians is analogous to the anterior pole of bilaterians. At the start of its life cycle a sea anemone exists as a free swimming planula, which then attaches to a surface and becomes a sea anemone. That free-swimming phase contains an apical tuft, a sensory structure at the front of the swimming animal’s body. The apical tuft is the part that attaches and becomes the aboral pole (the part distal from the mouth) of the adult anemone.

To test whether genetic expression in the aboral pole of cnidarians does in fact resemble the head patterning seen in bilaterians, the researchers analyzed gene expression in Nematostella vectensis, a sea anemone found in estuaries and bays. They focused on the six3 and FoxQ2 transcription factors, as these genes are known to regulate development of the anterior-posterior axis in bilaterian species. (six3 knockout mice, for example, fail to develop a forebrain, and in humans, six3 is known to regulate the development of forebrain and eyes.)

The N. vectensis genome contains one gene from the six3/6 group and four foxQ2 genes. Sinigaglia and colleagues found that Nvsix3/6 and one of the foxQ2 genes, NvFoxQ2a, were expressed predominantly on the aboral pole of the developing cnidarian but, after gastrulation, were excluded from a small spot in that region (NvSix3/6 was also expressed in a small number of other cells of the planula that resembled neurons). Because of this, the authors call NvSix3/6 and NvFoQ2a “ring genes”, and genes that are then expressed in that spot “spot genes.” The spot then develops into the apical tuft.

Through knockdown and rescue experiments, the researchers demonstrate that NvSix3/6 is required for the development of the aboral region; without it, the expression of spot genes is reduced or eliminated and the apical tuft of the planula doesn’t form. This suggests that development of the region distal from the cnidarian mouth appears to parallel the development of the bilaterian head.

This research demonstrates that at least a subset of the genes that cause head and brain formation in bilaterians are also differentially expressed in the aboral region of the sea urchin. The expression patterns are not identical to those in all bilaterians; however, the similarities suggest that the patterns of gene expression arose in an ancestor common to bilaterians and cnidarians, and that the process was then modified in bilaterians to produce a brain. So to answer the evolutionary question posed above, it seems that the developmental module that produces a head came first.

Researchers find that alcohol consumption damages brain’s support cells

Alcohol consumption affects the brain in multiple ways, ranging from acute changes in behavior to permanent molecular and functional alterations. The general consensus is that in the brain, alcohol targets mainly neurons. However, recent research suggests that other cells of the brain known as astrocytic glial cells or astrocytes are necessary for the rewarding effects of alcohol and the development of alcohol tolerance. The study, first-authored by Dr. Leonardo Pignataro, was published in the February 6th issue of the scientific journal Brain and Behavior.

"This is a fascinating result that we could have never anticipated. We know that astrocytes are the most abundant cell type in the central nervous system and that they are crucial for neuronal growth and survival, but so far, these cells had been thought to be involved only in brain’s support functions. Our results, however, show that astrocytes have an active role in alcohol tolerance and dependence," explains Dr. Pignataro.

The team of researchers from Columbia and Yale Universities analyzed how alcohol exposure changes gene expression in astrocyte cells and identified gene sets associated with stress, immune response, cell death, and lipid metabolism, which may have profound implications for normal neuronal activity in the brain. “Our findings may explain many of the long-term inflammatory and degenerative effects observed in the brain of alcoholics,” says Dr. Pignataro. “The change in gene expression observed in alcohol-exposed astrocytes supports the idea that some of the alcohol consumed reaches the brain and that ethanol (the active component of alcoholic beverages) is locally metabolized, increasing the production free radicals that react with cell components to affect the normal function of cells. This activates a cellular stress response in the cells in an attempt to defend from this chemical damage. On the other hand, the body recognizes these oxidized molecules as “foreign objects” generating an immune response against them that leads to the death of damage cells. This mechanism can explain the inflammatory degenerative process observed in the brain of chronic alcoholics, allowing for the development of different and novel therapeutically approaches to treat this disease” added Dr. Pignataro.

The consequences of alcohol on astrocytes revealed in this study go far beyond what happens to this particular cell type. Astrocytes play a crucial role in the CNS, supporting normal neuronal activity by maintaining homeostasis. Therefore, alcohol changes in gene expression in astrocytes may have profound implications for neuronal activity in the brain.

These findings will help scientists better understand alcohol-associated disorders, such as the brain neurodegenerative damage associated with chronic alcoholism and alcohol tolerance and dependence. “We hope that this newly discovered role of astrocytes will give scientists new targets other than neurons to develop novel therapies to treat alcoholism,” Leonardo Pignataro concluded.

Epigenetics: Neurons remember because they move genes in space

How do neurons store information about past events? In the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw, a mechanism unknown previously of memory traces formation has been discovered. It appears that at least some events are remembered thanks to… geometry.

Neurons are the most important cells of the nervous system. Scientists from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw have shown that during neuron stimulation permanent changes are observed with respect to genes’ arrangement within the cell nucleus. This discovery, reported in the “Journal of Neuroscience”, one of the most prestigious journals in the field of neurobiology, is significant for developing a better understanding of the processes going on in the mind and disorders of the nervous system, especially the brain.

“While conducting experiments on rats after epileptic seizures we have observed that a gene may permanently move deeper into the neuron’s cell nucleus. Since modification of the geometrical structure of the nucleus leads to changes in gene expression, this is how the neuron remembers, what happened”, explains Prof. Grzegorz Wilczyński from the Laboratory of Molecular and Systemic Neuromorphology at the Nencki Institute.

“Seq-ing” Insights into the Epigenetics of Neuronal Gene Regulation

The epigenetic control of neuronal gene expression patterns has emerged as an underlying regulatory mechanism for neuronal function, identity, and plasticity, in which short- to long-lasting adaptation is required to dynamically respond and process external stimuli. To achieve a comprehensive understanding of the physiology and pathology of the brain, it becomes essential to understand the mechanisms that regulate the epigenome and transcriptome in neurons. Here, we review recent advances in the study of regulated neuronal gene expression, which are dramatically expanding as a result of the development of new and powerful contemporary methodologies, based on next-generation sequencing. This flood of new information has already transformed our understanding of many biological processes and is now driving discoveries elucidating the molecular mechanisms of brain function in cognition, behavior, and disease and may also inform the study of neuronal identity, diversity, and neuronal reprogramming.

New chemical probe provides tool to investigate role of malignant brain tumor domains

In an article published as the cover story of the March 2013 issue of Nature Chemical Biology, Lindsey James, PhD, research assistant professor in the lab of Stephen Frye, Fred Eshelman Distinguished Professor in the UNC School of Pharmacy and member of the UNC Lineberger Comprehensive Cancer Center, announced the discovery of a chemical probe that can be used to investigate the L3MBTL3 methyl-lysine reader domain. The probe, named UNC1215, will provide researchers with a powerful tool to investigate the function of malignant brain tumor (MBT) domain proteins in biology and disease.

“Before this there were no known chemical probes for the more than 200 domains in the human genome that recognize methyl lysine. In that regard, it is a first in class compound. The goal is to use the chemical probe to understand the biology of the proteins that it targets,” said Dr. James.

Chromatin regulatory pathways play a fundamental role in gene expression and disease development, especially in the case of cancer. While many chemical probes work through the inhibition of enzyme activity, L3MBTL3 functions as a mediator of protein-to-protein interactions, which have been historically difficult to target with small, drug-like molecules.The researchers found three to four further disease subtypes within TN tumors, with more than 75 percent of the tumors falling into the basal-like subtype. Further research is needed to identify the distinct biomarkers shared by the expanded subtypes of TN cancers. The ultimate goal will be to target the individual biomarkers of these subtypes and create therapies that target their individual biology, according to Dr. Perou.

“Many people believe that protein-protein interactions are difficult to target. Often they have a large surface area, so it is hard for small molecules to go in and intervene,” said Dr. James.

Almost 40 percent of the genes that drive cancer can be mapped to dysfunction within signaling pathways. In the last five years, chemical probe development has allowed researchers to make fundamental observations of the role of these pathways in cancer development, as well as pointing to potential targets for new therapies. Each of the complex interactions within the signaling pathways represents a potential point where a therapy can be applied, and the probes allow researchers to interact with these processes at the molecular level and observe the overall effect of their perturbation on the disease state.

In a 2008 Nature Chemical Biology commentary, Dr. Frye outlined the qualities that make a good chemical probe. To Frye, a good chemical probe must be highly selective to enable specific questions to be asked and it must function as well in a cell as in the test tube, providing clear quantitative data with a well understood mechanism of action in either situation. It also must be available to all academic researchers without restrictions on its use, a criteria that the L3MBTL3 probe fulfills through the Frye lab’s commitment to provide researchers with the probe free of charge on request and UNC1215 is already available through commercial vendors as well.

Sleep Deprivation May Disrupt Your Genes

Far more than just leaving you yawning, a small amount of sleep deprivation disrupts the activity of genes, potentially affecting metabolism and other functions in the human body, a new study suggests.

It’s not clear how your health may be affected by the genetic disruption if you don’t get enough sleep. Still, the research raises the possibility that the effects of too little sleep could have long-lasting effects on your body.

"If people regularly restrict their sleep, it is possible that the disruption that we see … could have an impact over time that ultimately determines their health outcomes as they age in later life," said study co-author Simon Archer, who studies sleep at the University of Surrey, in England.

The study was published online Feb. 25 in the Proceedings of the National Academy of Sciences.

At issue is how a lack of enough sleep affects the human body. While it’s obvious that people get tired when they don’t sleep, scientists have only recently started to understand how sleep deprivation affects more than the brain, said Dr. Charles Czeisler, chief of the division of sleep medicine at Brigham and Women’s Hospital, in Boston. Research has suggested that sleep is important all the way down to the level of cells, said Czeisler, who was not involved in the new study.

For the study, researchers recruited 26 volunteers who spent a week getting a normal amount of sleep (8.5 hours) and a week getting less than normal (5.7 hours). The participants were still able to enter periods of deep sleep.

The researchers then studied the genes of the participants in blood samples and found that numerous genes, including some related to metabolism, became less active.

So what does that mean for the body? “We have no idea,” Archer said, “but these effects are not minor.” They appear to be similar to those that separate normal from abnormal types of tissue in the body, he said.

Archer said the next step will be to investigate how a lack of sleep affects the body in the long term and to figure out whether some kinds of people are more vulnerable to sleep deprivation’s negative effects on health.

For his part, Czeisler praised the study and said it raises the prospect of a blood test that will tell doctors if a patient’s body is being affected because he or she isn’t getting enough sleep. That’s important because substances such as caffeine can hide the effects of lack of sleep so patients don’t realize there’s a problem, he said.

What about the possibility of a pill that mimics the effects of sleep so people don’t have to bother getting some shut-eye in the first place? There’s no evidence to support the idea of such a pill, Czeisler said, although there’s ongoing research into how to improve the quality of sleep that people do manage to get.

(Image: iStock)

In research, it matters whether you’re a man or a mouse

Mice are poor stand-ins for people in experiments on some types of inflammation, a new study concludes. But some scientists say that critique discounts the value of mouse studies, many of which simply couldn’t be done without the animals.

More attention — and money — should go toward studying disease in people than on mouse research, a consortium of scientists contends online February 11 in the Proceedings of the National Academy of Sciences. Too often, researchers make a discovery in mice and assume that humans will react in the same way, says study coauthor Ronald Tompkins, chief of the Massachusetts General Hospital burn service. “The presumption is not justifiable,” he says. As a result, drug trials — often based heavily on data gleaned from studies with mice — can fail. 

But other scientists say that critique isn’t new and is overstated. Clinical trials are unsuccessful for many reasons, says Derry Roopenian, an immunologist and mouse geneticist at the Jackson Laboratory in Bar Harbor, Maine. “There’s frailty all along the process. That’s not a failure of the mouse.”

He and other critics worry that the study, conducted with a generic strain of laboratory mouse called Black6, unfairly tarnishes the reputation of all mice, even ones engineered to be as much like humans as possible. The group’s conclusions, were they accepted by policy makers, could set back biomedical research by jeopardizing funding for mouse studies, critics warn. “Without the mouse, progress is going to be slowed to a standstill,” Roopenian says.

Most of the researchers agree that creating mice with biologic responses that more closely mirror humans is important to understand diseases and develop new drugs. The sticking point appears to be how to balance mouse-based research with research involving humans.

Abnormal Brain Development in Fetuses of Obese Women

In a study to be presented on February 15 between 8 a.m. and 10 a.m. PST, at the Society for Maternal-Fetal Medicine’s annual meeting, The Pregnancy Meeting ™, in San Francisco, California, researchers from Tufts Medical Center will present findings showing the effects of maternal obesity on a fetus, specifically in the development of the brain.

The study, conducted at the Mother Infant Research Institute (MIRI) at Tufts Medical Center in Boston, Mass., looked at the fetal development of 16 pregnant women, eight obese and eight lean, to see what effects maternal obesity had on fetal gene expression. Researchers have found that fetuses of obese women had differences in gene expression as early as the second trimester, compared to fetuses of women who were a healthy weight. Of particular note were patterns of gene expression suggestive of abnormal brain development in fetuses of obese women.

During gestation, fetuses go through apoptosis, a developmental process of programmed cell death. However, fetuses of the obese women were observed to have decreased apoptosis, which is an important part of normal fetal neurodevelopment. Dr. Diana Bianchi, senior author of the study and executive director of MIRI, describes apoptosis as a pruning process, clearing out space for new growth.

“Women won’t be surprised to hear being obese while pregnant can lead to obesity in the child,” said Dr. Andrea Edlow, lead author of the study and fellow in Maternal-Fetal Medicine at Tufts Medical Center. “But what might surprise them is the potential effect it has on the brain development of their unborn child.”

It is too early to know the implications of their findings, but maternal obesity is a rapidly growing problem in the U.S., with one in three women being obese at conception. The conclusion of the study points to the role of gene expression studies such as this one in helping elucidate possible mechanisms for recently-described postnatal neurodevelopmental abnormalities in children of obese women, including increased rates of autism and altered hypothalamic appetite regulation.

Investigators’ Study Hints That Stem Cells Prepare for Maturity Much Earlier Than Anticipated

Unlike less versatile muscle or nerve cells, embryonic stem cells are by definition equipped to assume any cellular role. Scientists call this flexibility “pluripotency,” meaning that as an organism develops, stem cells must be ready at a moment’s notice to activate highly diverse gene expression programs used to turn them into blood, brain, or kidney cells.

Scientists from the lab of Stowers Investigator Ali Shilatifard, Ph.D., report in the December 27, 2012 online issue of Cell that one way cells stay so plastic is by stationing a protein called Ell3 at stretches of DNA known as “enhancers” required to activate a neighboring gene. Their findings suggest that Ell3 parked at the enhancer of a developmentally regulated gene, even one that is silent, primes it for future expression. This finding is significant as many of these same genes are abnormally switched on in cancer.

“We now know that some enhancer misregulation is involved in the pathogenesis of solid and hematological malignances,” says Shilatifard. “But a problem in the field has been how to identify inactive or poised enhancer elements. Our discovery that Ell3 interacts with enhancers in ES cells gives us a hand-hold to identify and to study them.”