To Get The Girl, You Have To Listen… No, Smell!

KC and the Sunshine band were prophetic when they wrote the song Get Down Tonight in ways that they never could have imagined. In the tiny social world of fruit fly courtship, the directive ‘do a little dance, make a little love’ is right on target. And just like in a dance club, what is said and when/how it is said are important to the success of fly hookups.

In ways not that dissimilar to humans, Drosophila melanogaster fruit flies meet at a singles bar commonly known as a fallen piece of overripe fruit. As the prospects congregate, there is a lot of information that is exchanged. Males use their wings to sing at short distances to the ladies milling about, giving persistent shouts of: (1) “Hey!” and (2) “How you doin’?”. When a female slows her pace to one of these calls from the dance floor, the male can then move in and cut out the ‘Hey’ portion of the call, and just use the more intimate “How you doin’?” signal. If she is still receptive, the male will dance a little closer, touching her butt and showing off his best moves until an eventual one-night-stand is awarded for his efforts. This interesting human/fruit fly parallel shows just how universal mating strategies are, even across 500 million years of evolution.

Also in similar fashion, when a miscommunication occurs, males have a much more difficult time obtaining a mate. The recent paper by Trott et al. (PLoS ONE, 2012) shows that the distance and timing of the two signals is critical to male mating success. Female fruit flies give off a chemical signal (like perfume!) to courting males, telling them that they’re interested, and the distance that the female lingers from the male is reinforcement to the male’s advances. Males who are deficient in their ability to smell due to an olfactory mutation also have a difficult time switching to a dominant “How you doin’?” signal. Without a functioning olfactory feedback mechanism, the male is unable to make the proper adjustments to his signal. For the female, it’s kind of like trying to have a one-on-one conversation with a male that is still trying to pick up every other female in the room. Even though the male is handsome/strong/free of parasites, interest from the female quickly wanes when he keeps giving the wrong signal. All the parts of the song are there; he just can’t read the cues.

So next time you’re out busting a move on the dance floor, think of the noble fruit fly passionately conducting it’s own miniature fandango. What is said is just as important as the moves that are made. And being able to read feedback is crucial to success. In a strange homage to Cyrano de Bergerac, it’s the male fruit fly that uses its ‘nose’ to speak sweet nothings that is best able to woo the female.

Trott AR, Donelson NC, Griffith LC, Ejima A (2012) Song Choice Is Modulated by Female Movement in Drosophila Males. PLoS ONE 7(9): e46025. doi:10.1371/journal.pone.0046025

Alexander Trott ’10 and postdocs Nathan Donelson and Aki Ejima worked on Drosophila courtship together with Prof. Leslie Griffith at Brandeis. Aki is now an Assistant Professor at Kyoto University. Alex is currently a graduate student at Harvard Medical School.

Video courtesy of Dr. Aki Ejima

Rodal to Receive NIH New Innovator Award

The NIH recently announced that Assistant Professor of Biology Avital Rodal will be a recipient of the 2012 NIH Directors New Innovator Award. The award allows new, exceptionally creative and ambitious investigators to begin high impact research projects. Granted to early stage investigators, candidates are eligible for the award for up to ten years after the completion of their PhD or MD. The award emphasizes bold, new approaches, which have the potential to spur large scientific steps forward. This year’s award was made to fifty-one researchers, and provides each with 1.5 million dollars of direct research funding over five years.

The Rodal lab studies the mechanisms of membrane deformation and endosomal traffic in neurons as they relate to growth signaling and disease. Membrane deformation by a core set of conserved protein complexes leads to the creation of tubules and vesicles from the plasma membrane and internal compartments. Endocytic vesicles contain, among other cargoes, activated growth factors and receptors, which traffic to the neuronal cell body to drive transcriptional responses (see movie). These growth cues somehow coordinate with neuronal activity to dramatically alter the morphology of the neuron, and disruptions to both endocytic pathways and neuronal activity have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer’s disease.

Dr. Rodal hopes to determine how neuronal activity affects the in vivo function and biochemical composition of the membrane trafficking machinery, by examining the transport of fluorescently labeled growth factor receptors in chronically or acutely activated neurons at the Drosophila neuromuscular junction (NMJ). Her group will combine these live imaging studies with a proteomic analysis of endocytic machinery purified from hyper-activated and under-activated neurons. By investigating the interplay between neuronal activity, membrane deformation, and receptor localization in live animal NMJs, she hopes to gain a better understanding of the strategies that healthy neurons employ to regulate membrane trafficking events, and provide new insight into specific points of failure in neurodegenerative disease.

Rosbash, Hall, and Young Honored with Canada Gairdner International Award

Brandeis science faculty members Michael Rosbash and Jeff Hall were named today as 2012 recipients of the Canada Gairdner International Award, one of the world’s top prizes for biomedical research. Together with Michael Young (Rockefeller Univ.), they were honored “for pioneering discoveries concerning the biological clock responsible for circadian rhythms”. The trio has previously been honored with the 2011 Louis Gross Horwitz Prize and the 2009 Gruber Neuroscience Prize for this research.

The Gairdner Foundation in Toronto began giving awards in 1959 to recognize and reward the world’s most creative and accomplished biomedical scientists. So far about a quarter of the recipients have gone on to win a Nobel Prize. Also honored this year (for other work) were neuroscientist Tom Jessell and immunologist Jeffrey Ravetch.

Hall is now Professor Emeritus of Biology, and his influence is felt strongly in the strong Drosophila genetics community at Brandeis even though his lab is gone. The Rosbash lab continues to be a force for innovation in research on circadian regulation and mRNA processing. To hear more about Rosbash lab research, come to Wednesday seminar on April 4, when Michael will be the speaker. The title of his seminar is: 37 years at Brandeis (but who’s counting): Gene Expression and Circadian Rhythms.

Here’s some video the Gairdner Foundation posted on YouTube:

More information about this story at the following sites:

Barrels, magnets, and flying insects

Bunch of new reviews by Brandeis authors in press, check one out if you need to catch up on the state of the art.

  • Lisman J, Yasuda R, Raghavachari S. Mechanisms of CaMKII action in long-term potentiation. Nat Rev Neurosci. 2012.
  • Griffith LC. Identifying behavioral circuits in Drosophila melanogaster: moving targets in a flying insect. Curr Opin Neurobiol. 2012.
  • Hedstrom L. The dynamic determinants of reaction specificity in the IMPDH/GMPR family of (beta/alpha)(8) barrel enzymes. Crit Rev Biochem Mol Biol. 2012.
  • Pan Y, Du X, Zhao F, Xu B. Magnetic nanoparticles for the manipulation of proteins and cells. Chem Soc Rev. 2012.

2012 Rosenstiel Award Recipient, Dr. Nahum Sonenberg

2012 Rosenstiel Award Lecture
Thursday, March 29, 2012, 4:00 PM
Gerstanzang 123

The 2012 Rosenstiel award winner, Dr. Nahum Sonenberg of McGill University, is a well-deserving recipient of this honor. Dr. Sonenberg received his Ph.D. in 1976 at the Weizman Institute of Science.  He then worked with Aaron Shatkin, where he discovered the translation initiation factor responsible for binding the 5’ cap of mRNA, eukaryotic Initiation Factor 4E (eIF4E); He has studied translation ever since.  Although his lab focuses on understanding how the cell achieves precise control of translation initiation, this line of investigation has led to discoveries affecting a wide variety of systems.  His lab has made key discoveries in cancer, obesity, virology, memory consolidation and how translation control plays a role in regulating these disparate processes.

In 1988, the Sonenberg lab made the groundbreaking discovery (Nature 1988, that the uncapped viral mRNA from poliovirus recruits the ribosome to internal regions of the 5’ untranslated region (UTR).  These sites have since been renamed internal ribosomal entry sites (IRESs). This finding was exciting since eukaryotic translation initiation typically requires the 5’ cap on an mRNA for eIF4E binding which subsequently recruits translation initiation machinery.  Until this time, the only mechanism of translation initiation was through the binding of eIF4E to the 5’ cap of mRNAs.  Sonenberg’s discovery that some mRNA has a mechanism to bypass the need for eIF4E binding and thereby avoiding translation control mechanisms started a new line of investigation in the translation field.  Along with discovering IRESs, this paper established an in vitro and an in vivo assay to study cap-independent translation initiation.  These assays are still used widely to test for IRES activity of mRNA UTRs.

Since that initial discovery, it has been found that many viruses contain IRES sequences in the UTR of mRNA that direct translation of viral proteins.  Some viruses, including poliovirus, are able to hijack eukaryotic translation machinery by cleaving factors necessary for canonical cap-dependent translation initiation, but dispensable for IRES translation. In this way, viral mRNAs are able to outcompete eukaryotic mRNAs for ribosome binding and in many cases become the most abundant transcript being translated.

Since the discovery of viral IRESs, many labs, including the Sonenberg lab, have discovered that some cellular genes also use IRESs to bypass the typical translation initiation control mechanisms. These genes are capable of translating even when the cell is actively shutting down translation.  One such cellular IRES-containing mRNA is the insulin receptor message, the IRES I study in the Marr lab.  Using assays similar to those first used in the 1988 paper published by the Sonenberg lab, I am exploring the necessity for the various initiation factors and IRES sequences required for efficient translation of insulin receptor in Drosophila melanogaster and mammalian cells.

The discovery that Dr. Sonenberg made in 1988 is only one example of the elegant research his lab has produced and continues to pursue.

Turn up the heat, flies still eat

A mystery has been unfolding at the intersection of pungent chemicals, temperate temperatures, and a question of detection: how do insects discriminate the noxious from the innocuous?  At the center is a single protein, TRPA1; however, this puzzle has implications from human pain to bug spray.

The subject of this story, TRPA1, is an ion channel gaining notoriety as an arbiter of agony.  From mollusks to mammals, TRPA1 is a biological irritant detector: it responds to pungent chemicals like those in mustard, wasabi, and garlic.  As we chop our onions and the tears flow, behind the scenes is TRPA1, gated by the reactive chemicals that waft into the air.  In fact, TRPA1 may lurk below the surface for many forms of irritation – the burn, the itch, the cough – and is implicated in maladies ranging from asthma, to inflammation, and pain.

In insects the story takes a twist, as TRPA1 mediates two senses.  On the one hand, TRPA1 in fruit flies and mosquitoes responds to the same chemicals that act on vertebrate orthologs.  In this role, TRPA1 stimulates gustatory neurons of the fly, detecting pungent chemicals and suppressing feeding before it is too late.

On the other hand, insect TRPA1 also responds to warmth.  Led by Brandeis University’s Paul Garrityour lab demonstrated previously that TRPA1 is essential for the fruit fly Drosophila melanogaster to select a comfortable temperature (~25C, ~77F).  Furthermore, our lab has demonstrated that TRPA1 is directly gated by warming (above ~27C, ~80F) acting as a molecular temperature sensor.

This brings us to the mystery: if Drosophila TRPA1 is activated by nasty chemicals and prevents flies from eating, and also gets activated by heating, how can a fly eat in the heat?

In a recent article published in the journal Nature, our lab reveals the mechanism.  We identified two isoforms (from alternate promoters) of Drosophila TRPA1.  The known isoform is gated by both pungent chemicals and warming.  However, we identified a new isoform that is selectively gated by chemicals. Check out Figure 1: neurons expressing the first isoform respond to both chemicals and temperature whereas neurons expressing the new isoform respond selectively to chemicals.

We also found that the temperature-insensitive form was expressed in the gustatory system of the fly, while the temperature-sensitive isoform is expressed inside the brain, so is shielded from chemicals.  In this way, the fly can eat in the heat because only a temperature-insensitive TRPA1 is modulating feeding.

The importance of distinguishing these two senses became clear when we mis-expressed the temperature sensitive isoform in aversive gustatory neurons.  When these engineered flies were gently warmed, they began to vomit uncontrollably, a dramatic demonstration of the behavioral imperative to distinguish noxious from innocuous stimuli.  Check out this video to see for yourself.

We then examined TRPA1 isoforms from malaria mosquitoes and found the same functional dichotomy observed in Drosophila.  This may explain how mosquitoes use a single channel to hunt for warm-bodied prey and avoid noxious repellents, and may provide two new targets for pest control: push on the chemical isoform to get bugs to leave you alone, or pull on the warmth-sensor to lure them to their death!

Beyond bug-sprays and bug-zappers, we have some tantalizing clues to how TRPA1 may further modulate its own temperature- and chemical-sensitivity.  The exact mechanisms are not clear but may have implications for the function of human TRPA1.  So, the mystery continues, but one thing is certain: TRPA1 promises to keep things spicy.

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