Drosophila Diaries: Sweet Sensations

 

By Michael Burel

 

Every graduate student has a contingency plan. You know, that thing you’d do if you were suddenly expelled from your program and no longer had semi-stale seminar pizza for sustenance. For me, that plan is to open a bakery. It’s a flawless idea. Everyone loves sweets (read: Everyone. Don’t let anyone fool you into thinking they don’t have a sweet tooth. They hide behind the thin ‘salty-food-is-better’ veil. Give them a cookie and see who is smiling now). And, as Ina Garten so famously chortled while sharing a recipe for irresistible chocolate chip cookies: “You can be miserable before you have a cookie and you can be miserable after you eat a cookie, but you can’t be miserable while you are eating a cookie.” Preach it, Ina.

 

But you know, sometimes a cookie just doesn’t cut it for graduate students. I mean, sure, on the outside we put on our big happy face (you know the one) and say through a forced grin, “Oh. Great. Seminar cookies…again. My favorite.” In reality, however, we do need actual food from time to time to exist on this planet. I’m talking about the kind of food that has vitamins (huh?), minerals (what are those?), fiber (like from a wicker basket?), and whole grains (isn’t that for cows?). In times of nutritional need, our bodies activate an intrinsic dowsing rod to hunt down food with the nutrients we desperately lack. That’s why patients with pica, a disorder characterized by an appetite for unusual things like sand and clay, often have a mineral deficiency: They seek these non-nutritive materials in a last-ditch attempt to restore, for example, a low iron count.

 

Now let me throw a wrench into the scheme: What if you couldn’t taste anything? How would your body know—in a time, let’s say, before we could scientifically determine the nutritional value of food—if something is good for you to eat? Indeed, animals that have lost the ability to taste still have preference for foods that are more nutritious and easier to digest (1, 2). But how?

 

In search for an answer, and for the second installment of Drosophila Diaries, scientists hunted for a gene in Drosophila that would abolish a fly’s ability to distinguish what is nutritionally beneficial from what is not. Monica Dus et al. led a study to really understand how animals blind to taste can still select the more nutritionally appropriate food choice, an ability that is potently augmented in times of starvation. At the core of their research was a genetic screen in otherwise normal, healthy flies to find a mutation that would prevent them from choosing a good sugar (the metabolically active D-glucose) from a bad sugar (the unusable L-glucose). They honed down on such a gene and named it—quite cutely—cupcake, which only seems appropriate: Put a cupcake and a bowl of bran flakes in front of a five-year-old and they will 99% of the time choose the cupcake. Nutritionally the best option? No. The more delicious, magical of the two? Absolutely.

 

The cupcake gene encodes a sodium/solute co-transporter whose mammalian ortholog works to move glucose across the small intestine into blood. Obviously, cupcake must be doing the same thing in flies: Without cupcake, flies can’t take up sugar into their hemolymph (bug blood) and therefore can’t sense the food’s nutritional value. A fly gives up all hope of even picking one sugar over another because, to the mutant, it’s all the same.

 

If only it were that simple.

 

You see, cupcake isn’t even expressed in fly guts. The group found that cupcake is expressed only in a very select group of neurons in the fly brain in a structure called the ellipsoid body. The ellipsoid body is part of a larger brain structure called the central complex, which modulates fly behavior and—quite intriguingly—processes the senses. By specifically putting cupcake back in these neurons, the authors rescued the ability of flies to sense which sugar was best for them. How cupcake works in these neurons to sense appropriate glucose still remains a mystery.

 

As graduate students, we often come face to face with difficult decisions: Should I attend this conference or get data for my upcoming committee meeting? Should I run this Western now or wait until Monday? And perhaps the most important of all: Should I pick the oatmeal raisin cookies or the random deli salad for seminar munchies? (Obviously the former). Too often, we subsist on foods that aren’t the best for us yet are readily available. I can’t help but wonder if it’s because we all have a little hypomorphic cupcake in us.

 

Which works for me, because my bakery business would be booming. Science wins again.

 

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On Cheap Dates and cheapdate

By Michael Burel

As a graduate student, I don’t have many chances to go on dates. My definition of a good “date” would be my fruit flies and I taking a romantic walk on the beach, sipping fine Italian wine, and getting perfect experimental results on a Saturday night. And by those standards, I’ve gone on a lot of bad dates.

You’ll have to forgive me, then, if I don’t know what constitutes a “cheap date.” So, by peeking over my shoulder to ensure my baymate couldn’t see what I was shamelessly about to Google, I searched “define: cheap date.” I was unsurprisingly led to Urban Dictionary, whose definitions of (*ahem*) colorful terms I’ve never heard of—even while walking the streets of New York City—remain suspect at best. But I did end up finding a palatable definition for what a cheap date really is: “A person who has a low tolerance for alcohol and becomes intoxicated quickly after relatively few drinks.

By that definition, scientists sure got it right this time. In honor of Valentine’s Day, I would like to open this first segment of Drosophila Diaries with the Drosophila melanogaster gene, cheapdate. Yes, scientists may receive a tremendous amount of erroneous flack for being painfully logical and uptight (I’m looking at you, Big Bang Theory). If you are in search for a humorous reprieve, however, look no further than the gems that are Drosophila genes, which are named after their mutation-induced phenotypes. It’s a chance for scientists to leave a lasting impression and mentally quip, “Thank you, thank you, I’ll be here all night!” as if at a stand-up comedy club where colleagues roar with laughter at clever genetic knee-slappers. To each their own.

So how did the cheapdate gene get its name? In 1998, Monica Moore and colleagues performed a genetic screen in Drosophila in order to identify genes that affect alcohol sensitivity. Fruit flies, with their astounding genetic tractability, offer a chance to understand how mutations in genes and their resulting dysfunctional proteins cause observable changes in animal behavior (a feat cell culture does not allow…unless you count annoying contamination as an acquired skill akin to acrobatics, a point I will beg to differ to my grave).

I know, I know, I can hear you now: “Wait…so you mean they looked for genes that made flies act like a lightweight? How do you even tell if a fly is drunk?” Enter the inebriometer: A torture-chamber sounding device that is actually a vertical glass tube filled with several meshed rings on which flies can perch. Controlled concentrations of ethanol vapor diffuse throughout the tube, and as time goes by, flies get tipsy, lose motor coordination, and fall off the mesh. Think like the traditional “walk and turn” field sobriety test for drunk drivers, but instead of shouting sloppy profanities and getting arrested, flies are simply measured for how quickly they fall down.

In their screen, Moore et al. identified a particular gene that caused “inebriated” flies to fall faster than wild-type flies. They determined that this gene was actually an allele of the already discovered gene amnesiac, which plays a role in associative memory and encodes a protein that increases levels of cAMP. Moore et al. reasoned that cAMP levels were jeopardized in cheapdate-mutant flies. Indeed, by bolstering cAMP back to normal, they were able to sober up cheapdate mutants, watching them perch with all the dignity and grace that comes with balancing delicately on a wire-like lining while knocking a few back. By the way, did I mention cAMP signaling levels are altered in cells from alcoholic patients (1, 2)? Yeah, turns out fruit flies are actually good for something.

So this Valentine’s Day, if you are wining and dining a special someone (or preparing to snuggle up solo with a big bottle of Pinot like myself), remember that if your final bill comes out mysteriously discounted, you may have cheapdate to thank.

 

Leafing through the Literature

Thalyana Smith-Vikos

Highlighting recently published articles in molecular biology, genetics, and other hot topics

Can I get some of your gut bacteria?

While there have been many reports popping up in the literature that demonstrate a connection between gut microbiome and diet, Ridaura et al. have elegantly showed how the mammalian microbiome affects diet in a specific yet alterable manner that can be transmitted across individuals. The researchers transplanted fecal microbiota from adult murine female twins (one obsess, one lean) into mice fed diets of varying levels of saturated fats, fruits and vegetables. Body and fat mass did depend on fecal bacterial composition. Strikingly, mice that had been given the obese twin’s microbiota did not develop an increase in body mass or obesity-related phenotypes when situated next to mice that had been given the lean twin’s microbiota. The researchers saw that, for certain diets, there was a transmission of specific bacteria from the lean mouse to the obese mouse’s microbiota.

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In vivo reprogramming

Abad et al. have performed reprogramming of adult cells into induced pluripotent stem cells (iPSCs) in vivo. By activating the transcription factor cocktail of Oct4, Sox2, Klf4 and c-Myc in mice, the researchers observed teratomas forming in multiple organs, and the pluripotency marker NANOG was expressed in the stomach, intestine, pancreas and kidney. Hematopoietic cells were also de-differentiated via bone marrow transplantation. Additionally, the iPSCs generated in vivo were more similar to embryonic stem cells than in vitro iPSCs by comparing transcriptomes. The authors also report that in vivo iPSCs display totipotency features.

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Connection between pluripotency and embryonic development

Lee and colleagues have discovered that some of the same pluripotency factors (Nanog, Oct4/Pou5f1 and SoxB1) are also required for the transition from maternal to zygotic gene activation in early development. Using zebrafish as a model, the authors identified several hundred genes that are activated during this transition period, which is required for gastrulation and removal of maternal mRNAs in the zebrafish embryo. In fact, nanogsox19b and pou5f1 were the top translated transcription factors prior to this transition, and a triple knockdown prevented embryonic development, as well as the activation of many zygotic genes. One of the genes that failed to activate was miR-430, which the authors have previously shown is required for the maternal to zygotic transition. Thus, Nanog, Oct4 and SoxB1 induce the maternal to zygotic transition by activating miR-430.

 

A microRNA promotes sugar stability

Pederson and colleagues report that a C. elegans microRNA, miR-79, targets two factors critical for proteoglycan biosynthesis, namely a chondroitin synthesis and a uridine 5′-diphosphate-sugar transporter. Loss-of-function mir-79 mutants display neurodevelopmental abnormalities due to altered expression of these biosynthesis factors. The researchers discovered that this dysregulation of the two miR-79 targets leads to a disruption of neuronal migration through the glypican pathway, identifying the crucial impact of this conserved microRNA on proteoglycan homeostasis.

Struggling to keep up with all the mIRs? Create your feed for miR-430 or miR-79.

 

Establishing heterochromatin in Drosophila

It is known that RNAi and heterochromatin factor HP1 are required for organizing heterochromatin structures and silencing transposons in S. pombe. Gu and Elgin built on this information by studying loss of function mutants and shRNA lines of genes of interest in an animal model, Drosophila, during early and late development. The Piwi protein (involved in piRNA function) appeared to only be required in early embryonic stages for silencing chromatin in somatic cells.  Loss of Piwi leads to decreased HP1a, and the authors concluded that Piwi targets HP1a when heterochromatin structures are first established, but this targeting does not continue in later cell divisions. However, HP1a was required for primary assembly of heterochromatin structures and maintenance during subsequent cell divisions.

 

The glutamate receptor has a role in Alzheimer’s

Um and colleagues conducted a screen of transmembrane postsynaptic density proteins that might be able to couple amyloid-β oligomers (Aβo) bound by cellular prion protein (PrPC) with Fyn kinase, which disrupts synapses and triggers Alzheimer’s when activated by Aβo-PrPC . The researchers found that only the metabotropic glutamate receptor, mGluR5, allowed Aβo-PrPC  to activate intracellular Fyn. They further showed a physical interaction between PrPC and mGluR5, and that Fyn is found in complex with mGluR5. In Xenopus oocytes and neurons, Aβo-PrPC caused an increase in intracellular calcium dependent on mGluR5. Further, the Aβo-PrPC-mGluR5 complex resulted in dendritic spine loss. As a possible therapeutic, an mGluR5 antagonist given to a mouse model of inherited Alzheimer’s reversed the loss in synapse density and recovered learning and memory loss.

 

Keep playing those video games!

Anguera et al. investigated whether multitasking abilities can be improved in aging individuals, as these skills have become increasingly necessary in today’s world. The scientists developed a video game called NeuroRacer to test multitasking performance on individuals aged 20 to 79, and they observed that there is an initial decline in this ability with age. However, by playing a version of NeuroRacer in a multitasking training mode, individuals aged 60-85 achieved levels higher than that of 20-year-olds who had not used the training mode, and these successes persisted over the course of 6 months. This training in older adults improved cognitive control, attention and memory, and the enhancement in multitasking was still apparent 6 months later. The results from playing this video game indicate that the cognitive control system in the brains of aging individuals can be improved with simple training.

Want to stay in the game? Create your feeds and stay current with what’s sizzling.

 

Leafing through the Literature

Thalyana Smith-Vikos

Avian Influenza Transmission in Mammals

Avian influenza viruses can reassort their genomes to infect mammals. To investigate how this is done, Zhang et al. generated all possible 127 reassorted viruses by combining the hemagglutinin gene of an avian H5N1 influenza virus with an H1N1 virus capable of infecting humans. The researchers examined the virulence of these viruses in mice, as well as their ability to transmit in guinea pigs, which, like certain livestock, have both avian and mammalian airway receptors. Certain H1N1 genes allowed the H5N1 virus to transmit between guinea pigs. The virus was transferred by respiration between guinea pigs without killing them, indicating that livestock could be carriers of this virus without the farmer even knowing. Continue reading “Leafing through the Literature”