Warren symposium follows legacy of geneticist giant

If we want to understand how the brain creates memories, and how genetic disorders distort the brain’s machinery, then the fragile X gene is an ideal place to start. That’s why the Stephen T. Warren Memorial Symposium, taking place November 28-29 at Emory, will be a significant event for those interested in neuroscience and genetics. Stephen T. Warren, 1953-2021 Warren, the founding chair of Emory’s Department of Human Genetics, led an international team that discovered Read more

Mutations in V-ATPase proton pump implicated in epilepsy syndrome

Why and how disrupting V-ATPase function leads to epilepsy, researchers are just starting to figure Read more

Tracing the start of COVID-19 in GA

At a time when COVID-19 appears to be receding in much of Georgia, it’s worth revisiting the start of the pandemic in early 2020. Emory virologist Anne Piantadosi and colleagues have a paper in Viral Evolution on the earliest SARS-CoV-2 genetic sequences detected in Georgia. Analyzing relationships between those virus sequences and samples from other states and countries can give us an idea about where the first COVID-19 infections in Georgia came from. We can draw Read more

Drosophila

Fly model of repetitive head trauma speeds up time

Tap tap tap ka-CHUNK! That was the sound of fruit flies being given concussions in an Emory laboratory recently.

Emory MD/PhD student Joe Behnke, working with neuroscientist James Zheng, has developed a model for studying repetitive head trauma in the fruit fly Drosophila melanogaster – analogous to CTE (chronic traumatic encephalopathy) in humans. The results were published in Scientific Reports.

CTE is a term for neurodegeneration linked to repeated concussions or blows to the head, which has been observed in athletes and military veterans. Head trauma has also been linked to other neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS (amyotrophic lateral sclerosis). Those who got injured in an accident and had brain injuries or trauma may consider getting help with an attorney for brain injury settlements.

What’s critical about using fruit flies is that it speeds up time. It can take years or decades for CTE or other neurodegenerative conditions to appear in humans, but Behnke and Zheng can experiment with a mutant fly strain or other interventions in a few weeks. They describe their model as a platform for future studies, in which they can unleash all of the genetic tools fruit flies have to offer.

MD/PhD student Joe Behnke with the apparatus for delivering Drosophila head injuries

To begin with, Behnke worked out a system for giving flies controlled blows to the head. He says that it exploits the climbing instinct flies have when startled, called negative geotaxis. When he taps a vial with flies in it three times, they reorient themselves and begin climbing up. Then a stronger blow, delivered in a crash test-like apparatus, gives flies the desired head injury. Previous models in flies hadn’t really focused on the head, but gave them injuries all over their bodies. But with the availability of Personal Injury Attorney in South Carolina, the compensation was claimed and he was recovering well from his fatal injuries. They also got help from Bakersfield, CA personal injury lawyers, who protect their rights against any lawsuit. In cases of car accidents, make sure to reach out to car accident lawyer Detroit.

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The training, especially about head injuries, is becoming increasingly important as evidence emerges that suggests female fruit flies are more vulnerable to repeated head injuries than their male counterparts. Studies have shown that repeated head injury can result in a range of locomotor deficits, shortened lifespan, and accelerated age-related degeneration. Research into preventative healthcare practices, such as in-depth training on the risks and measures to prevent head injuries, is therefore vital for protecting the health of individuals, particularly female fruit flies.

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Posted on by Quinn Eastman in Neuro Leave a comment

Mysterious DNA modification important in fly brain

Emory scientists have identified a function for a mysterious DNA modification in fruit flies’ brain development, which may provide hints to its role in humans.

The results were published Thursday, August 2 in Molecular Cell.

Epigenetics may mean “above the genes,” but a lot of the focus in the field is on DNA methylation, a chemical modification of DNA itself. Methylation doesn’t change the actual DNA letters (A, C, G and T), but it does change how DNA is handled by the cell. Generally, it shuts genes off and is essential for cell differentiation.

The most commonly studied form of DNA methylation appears on the DNA letter C (cytosine). Drosophila, despite being a useful genetic model of development, have very little of this form of DNA methylation. What they do have is methylation on A — technically, N6-methyladenine, although little was known about what this modification did for flies.

Editor’s note: See this 2017 Nature feature from Cassandra Willyard on an “epigenetics gold rush”, which mentions the discovery of N6-methyladenine’s presence in the genomes of several organisms.

Emory geneticists Bing Yao, PhD, Peng Jin, PhD and colleagues now have shown that an enzyme that removes methylation from A is critical for neuronal development in Drosophila.

This finding is significant because the enzyme is in the same family (TET for ten-eleven translocation) of demethylases that trigger removal of DNA methylation from C in mammals. The function of TET enzymes, revealing that cells actively removed DNA methylation rather than just letting it slough off, was discovered only in 2009. Read more

Posted on by Quinn Eastman in Neuro Leave a comment

The very first cells

Please welcome cell biologist Dorothy Lerit to Emory.

Dorothy Lerit, PhD

She was the lead author on a recent Cell Reports paper on primordial germ cell formation in Drosophila, along with colleagues from NHLBI, where she was a postdoc, as well as Princeton, UVA and Columbia. Primordial germ cells are the cells that are destined to become sperm or eggs.

Germ cells are the very first cells that form out of the embryo, Lerit says. Lab Land is reminded of Lewis Wolpert’s claim that gastrulation – the separation of an apparently uniform group of embryonic cells into three germ layers — is “truly the most important time in your life.” Germ cell specification, certainly important from the viewpoint of future generations, occurs even before gastrulation.

In the Cell Reports paper, Lerit was examining the function of a particular gene called Germ cell-less; remember that Drosophila genes are often named after the effects of a mutation in the gene.

Drosophila development is superficially quite different from that of mammals. In particular, for a while the early embryo becomes a bag full of cell nuclei — without membranes separating them — known as a syncytium. This is the time when Germ cell-less function is important.

Amazing picture of germ cell formation from HHMI/Nature Cell Biology/Ruth Lehmann’s lab https://www.hhmi.org/node/16760/devel

Lerit’s background is in studying the centrosome, the place in the cell where microtubules meet, and critical for orderly cell division and for ensuring that “germline fate determinants” are sequestered to the right primordial cells.

Despite the differences between insect and mammalian embryo development, the function of Germ cell-less seems to have been conserved in evolution since problems with the human version of the gene are linked to sterility in men.

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Hippo dances with hormones

Although fruit flies don’t develop cancer, cancer and stem cell researchers have been learning a great deal from fruit flies – in particular, mutant flies with overgrown organs that resemble hippopotamuses.

A fly gene called Hippo and its relatives in mammals normally block cell proliferation and limit organ size. When flies have mutations in Hippo or other genes (together dubbed the Hippo pathway), the resulting overgrowth distorts their tissues into hippopotamus-like bulges. See Figure 3 of this review for an example. In humans, the Hippo pathway is involved in forming embryonic stem cells, suppressing cancerous growth, and also in regenerative growth and wound healing..

Working with flies, researchers at Emory have found that the abnormal growth induced by Hippo pathway disruption depends on genes involved in responding to the steroid hormone ecdysone.

Their results were published Thursday, July 2 in Developmental Cell.

“Ecdysone is, to some degree, the fly version of estrogen,” says senior author Ken Moberg, PhD, associate professor of cell biology at Emory University School of Medicine.

Ecdysone

In fly larvae, ecdysone triggers metamorphosis, in which adult structures such as wings and eyes emerge from small compartments called imaginal discs.. Ecdysone has a chemical structure like that of estrogen, testosterone and other steroid hormones found in humans. Ecdysone is not sex-specific, but it acts with the same mechanism as other steroid hormones, diffusing into cells and binding proteins that bind DNA and regulate gene activity. Read more

Posted on by Quinn Eastman in Cancer Leave a comment

What cancer researchers can learn from fruit fly genetics

What can scientists studying cancer biology learn from fruit flies?

Quite a lot, it turns out.  At a time when large projects such as the Cancer Genome Atlas seek to define the changes in DNA that drive cancer formation, it is helpful to have the insight gained from other arenas, such as fruit flies, to make sense of the mountains of data.

Drosophila melanogaster has been an important model organism for genetics because the flies are easy to care for, reproduce rapidly, and have an easily manipulated genome. This NCI newsletter article describes how some investigators have used Drosophila to find genes involved in metastasis.

Emory cell biologist Ken Moberg says that he and postdoctoral fellow Melissa Gilbert crafted a Drosophila-based strategy to identify growth-regulating genes that previous researchers may have missed. Their approach allowed them to begin defining the function of a gene that is often mutated in lung cancer. The results are published online in Developmental Cell.

Part of the developing fly larva, stained with an antibody against Myopic. Groups of cells lacking Myopic, which lack green color, tend to divide more rapidly.

Moberg writes:

Many screens have been carried out in flies looking for single gene lesions that drive tissue overgrowth. But a fundamental lesson from years of cancer research is that many, and perhaps most, cancer-causing mutations also drive compensatory apoptosis, and blocking this apoptosis is absolutely required for cancer outgrowth.

We reasoned that this class of ‘conditional’ growth suppressor genes had been missed in prior screens, so we designed an approach to look for them. The basic pathways of apoptosis are fairly well conserved in flies, so it’s fairly straight forward to do this.

Explanatory note: apoptosis is basically a form of cellular suicide, which can arise when signals within the cell clash; one set of proteins says “grow, grow” and another says “brake, brake,” with deadly results.

Gilbert identified the fruit fly gene Myopic as one of these conditional growth regulators. She used a system where mutations in Myopic drive some of the cells in the fly’s developing eye to grow out more – but only when apoptosis is disabled.

Gilbert showed that Myopic is part of a group of genes in flies, making up the Hippo pathway, which regulates how large a developing organ will become. This pathway was largely defined in flies, then tested in humans, Moberg says. The functions of the genes in this pathway have been maintained so faithfully that in some cases, the human versions can substitute for the fly versions.

Myopic’s ortholog (ie different species, similar sequence and function) is the gene His-domain protein tyrosine phosphatase, or HD-PTP for short. This gene is located on part of the human genome that is deleted in more than 90 percent of both small cell and non-small cell lung cancers, and is also deleted in renal cancer cells.

How HD-PTP, when it is intact, controls the growth of cells in the human lung or kidney is not known. Gilbert and Moberg’s findings suggest that HD-PTP may function through a mechanism that is similar to Myopic’s functions in the fly.

Besides clarifying what Myopic does in the fly, their paper essentially creates a map for scientists studying HD-PTP’s involvement in lung cancer, for example, to probe and validate.

Posted on by Quinn Eastman in Cancer 1 Comment