Zebrafish and Humans Don’t See Eye-to-Eye on Steroids
If you have an aquarium there’s a good chance there are zebrafish (Danio rerio) swimming in the water. These 4-centimeters-long tropical fish are a staple among fish enthusiasts because of their resiliency. In science, zebrafish are an important animal model for studying genetics and disease and are widely employed in for drug discovery.
In fact, in 2017 a group of researchers published a paper in PNAS in which they demonstrated success in using zebrafish models to personalize drugs for cancer treatment. Upon reading this, Michael Baker, PhD, Distinguished Research Professor Emeritus at UC San Diego School of Medicine, and Yoshinao Katsu, PhD, at Hokkaido University in Sapporo, Japan, who had also been studying the species, published a response letter applauding the benefits of the zebrafish model for assessing the effects of drugs on tumor growth to identify personalized cancer treatments.
But Baker and Katsu also advised caution, noting that the PNAS paper did not account for the unexpected activation of the zebrafish mineralocorticoid receptor by progesterone, an important reproductive steroid. Although, the human mineralocorticoid receptor senses several steroid hormones that activate gene expression, progesterone is not one of these activators.
Zebrafish embryo, courtesy of National Institute of General Medical Sciences
In humans, progesterone acts as an antagonist, inhibiting activation of the mineralocorticoid receptor by aldosterone. In people and other terrestrial vertebrates, aldosterone is the principle activator of the mineralocorticoid receptor.
In a new study published in Science Signaling in July, Baker and Katsu, along with Kaori Oka at Hokkaido University, expand on the difference in activation of mineralocorticoid receptors in human, chicken, alligator, frog and zebrafish models. In humans, activation of the mineralocorticoid receptor by aldosterone regulates sodium and potassium levels in the blood. For this reason, activation of the mineralocorticoid receptor is a target of angiotensin-converting enzyme (ACE) inhibitors for lowering blood pressure. Progesterone does not activate human mineralocorticoid receptor. Instead, progesterone acts as a reproductive hormone in humans and is also involved in the growth of some hormone-dependent tumors.
Aldosterone is not synthesized by fish, which motivated Baker and Katsu to look at other steroids, including cortisol and deoxycorticosterone, which have been previously proposed as activators of the mineralocorticoid receptor. However, based on their research, they advanced a novel hypothesis that progesterone is the physiological regulator of the mineralocorticoid receptor in zebrafish.
“In zebrafish, progesterone plays a dual role in affecting transcriptional activation of both the mineralocorticoid receptor and the progesterone receptor, which is of interest to endocrinologists and evolutionary biologists,” said Baker. “There appears to be a selective advantage to this duality, although at this time, the selective advantage is unknown. Deciphering the role of progesterone’s interaction with human and fish mineralocorticoid receptors can yield important information for treating human diseases.”
- Yadira Galindo
Sand and other granular materials can be strikingly fluid-like. Here the impact of a solid sphere on sand generates a splash remarkably similar to what’s seen with water. When the ball hits, it creates a crater in the surface and sends up a bowl-like spray of sand. As the ball continues falling through the sand, the grains try to fill the empty space left behind. The walls of sand collapsing around the void meet somewhere between the surface and the depth of the ball. This generates the tall jet we observe, as well as a second one under the surface that we can’t see. We know that collapse traps an air bubble under the surface because of the eruption that occurs as the jet falls. That’s the air bubble reaching the surface. (Image credit: T. Nguyen et al., source; see also R. Mikkelsen et al.)
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Brain Cells Found to Control Aging
Scientists at Albert Einstein College of Medicine have found that stem cells in the brain’s hypothalamus govern how fast aging occurs in the body. The finding, made in mice, could lead to new strategies for warding off age-related diseases and extending lifespan. The paper was published online in Nature.
The hypothalamus was known to regulate important processes including growth, development, reproduction and metabolism. In a 2013 Nature paper, Einstein researchers made the surprising finding that the hypothalamus also regulates aging throughout the body. Now, the scientists have pinpointed the cells in the hypothalamus that control aging: a tiny population of adult neural stem cells, which were known to be responsible for forming new brain neurons.
“Our research shows that the number of hypothalamic neural stem cells naturally declines over the life of the animal, and this decline accelerates aging,” says senior author Dongsheng Cai, M.D., Ph.D., professor of molecular pharmacology at Einstein. “But we also found that the effects of this loss are not irreversible. By replenishing these stem cells or the molecules they produce, it’s possible to slow and even reverse various aspects of aging throughout the body.”
In studying whether stem cells in the hypothalamus held the key to aging, the researchers first looked at the fate of those cells as healthy mice got older. The number of hypothalamic stem cells began to diminish when the animals reached about 10 months, which is several months before the usual signs of aging start appearing. “By old age—about two years of age in mice—most of those cells were gone,” says Dr. Cai.
The researchers next wanted to learn whether this progressive loss of stem cells was actually causing aging and was not just associated with it. So they observed what happened when they selectively disrupted the hypothalamic stem cells in middle-aged mice. “This disruption greatly accelerated aging compared with control mice, and those animals with disrupted stem cells died earlier than normal,” says Dr. Cai.
Could adding stem cells to the hypothalamus counteract aging? To answer that question, the researchers injected hypothalamic stem cells into the brains of middle-aged mice whose stem cells had been destroyed as well as into the brains of normal old mice. In both groups of animals, the treatment slowed or reversed various measures of aging.
Dr. Cai and his colleagues found that the hypothalamic stem cells appear to exert their anti-aging effects by releasing molecules called microRNAs (miRNAs). They are not involved in protein synthesis but instead play key roles in regulating gene expression. miRNAs are packaged inside tiny particles called exosomes, which hypothalamic stem cells release into the cerebrospinal fluid of mice.
The researchers extracted miRNA-containing exosomes from hypothalamic stem cells and injected them into the cerebrospinal fluid of two groups of mice: middle-aged mice whose hypothalamic stem cells had been destroyed and normal middle-aged mice. This treatment significantly slowed aging in both groups of animals as measured by tissue analysis and behavioral testing that involved assessing changes in the animals’ muscle endurance, coordination, social behavior and cognitive ability.
The researchers are now trying to identify the particular populations of microRNAs and perhaps other factors secreted by these stem cells that are responsible for these anti-aging effects—a first step toward possibly slowing the aging process and treating age-related diseases.
Road salt is polluting waterways
Image credit: Ryan Utz/Chatham University
Salt may work well to de-ice streets and sidewalks in winter, but it can create big problems for lakes, rivers and streams. Now researchers have found that bodies of water are becoming more alkaline, the “opposite” of acidic, as a result of salt pollution from highway runoff.
(Image caption: Image shows neurons from the cingulate cortex of mouse brain. Credit: Wikimedia Commons)
It remains unclear to scientists why almost every RNA-binding protein has a sibling – or “paralog.” While such sibling proteins have the same origins and are similar to each other in a number of ways, they are presumed to fulfill different functions in the cell.
Focusing on two such sibling RNA-binding proteins – PTBP1 and PTBP2 – that are important for the nervous system, a team of researchers has found that these proteins serve both redundant and unique functions in the developing brain when neural stem cells are changed into neurons – cells that process and transmit information through electrical and chemical signals.
“PTBP1 is expressed in neural stem cells, and PTBP2 in differentiating neurons,” said Sika Zheng, an assistant professor of biomedical sciences in the School of Medicine at the University of California, Riverside, who led the research project. “Their expressions are almost mutually exclusive. During brain development, cells switch expression of PTBP1 to PTBP2. This contributes to the neuronal differentiating process, and can offer us insights into understanding what makes a neuron a neuron.”
Study results appear Dec. 6 in Cell Reports.
The research, done using multiple mouse models, has implications for fine-tuning stem cell therapeutic strategies for neurologic disorders such as stroke, ALS, and Parkinson’s disease.
Zheng explained that in humans it normally takes months to differentiate a stem cell into a neuron. “Understanding at the molecular level how these proteins work and how neurons acquire their building blocks can help us speed up the differentiation process and make it more efficient,” he said.
He explained that PTBP1 and PTBP2 could be visualized as siblings who are both born musicians, except that PTBP1 is a master of classical music, while PTBP2 masters contemporary music.
“One can imagine that both like music and sometimes perform a piece in the same way,” Zheng said. “But at other times they interpret and play the music differently, for example, with different styles and instruments, giving the same score different meanings and emotions. In this analogy, the musical scores are primitive genetic messages or premature RNA in a cell.”
Premature RNA is an unprocessed RNA molecule that is “copied” from a DNA template in the cell nucleus. Premature RNA undergoes extensive modification via the aid of RNA binding proteins to produce the mature RNA genetic message. Depending on how the modification is conducted, the same premature RNA can be processed differently to create variants of the final RNA product. The compositions of all mature RNA within a cell collectively determine the cell identity.
“Using the same analogy, the performance is the final product or mature RNA,” Zheng continued. “Neural stem cells and neurons have somewhat different collections of RNA thanks to the activity of PTBP1 and PTBP2.”