Rodal lab find surprising new link between inflammation and Lowe Syndrome

Could a disease with symptoms in the brain, eyes, and kidneys actually be caused by problems with immune cells? A team of scientists from the Rodal Lab, co-first authored by Steven Del Signore and Sarah Biber and including three Brandeis undergraduates (Katy Lehmann ‘16, Stephanie Heimler ‘17, and Ben Rosenfeld ’18), think this just might be the case with Lowe Syndrome, in a new paper published Oct 13th in PLOS Genetics.

Patients with Lowe Syndrome suffer from kidney failure, congenital cataracts, and several neurological problems including intellectual disability and seizures. Scientists have known for some time that the disease is caused by mutations in a gene called OCRL, but remain unsure how its loss causes such a diverse array of symptoms. A big problem has been that OCRL appears to do many different jobs inside cells, including controlling how they divide, how they sense their surroundings, and how they store and transport materials inside small packages called endosomes.

Fly immune cells showing the tracks of moving endosomes. Single tracks represent the path of individual endosomes over time.

To try to solve this mystery, a team of researchers from the Rodal lab used the fruit fly, which has its own version of the OCRL gene and allowed the investigators to perform powerful genetic experiments to figure out precisely what OCRL is doing, and where. To do this, the group created a fly missing its OCRL gene. They were surprised to find that, rather than eye or neurological defects, loss of OCRL hyper-activated cells of the innate immune system. The innate immune system is the first line of defense against infection in humans (and the only defense in fruit flies), when cells release inflammatory signals that mobilize specialized cells to attack invading pathogens.

The team determined that OCRL is required in one of these specialized immune cells in the fly, and that the immune-cell activation was caused by problems in a particular step of intracellular transport. Every cell of the body has its own postal service, which is used to pack and ship signals that tell the cell or its neighbors to grow, divide, or jump into action (see movie here to watch endosomes moving inside living fly immune cells). The OCRL mutant immune cells had a problem in a key step that controls whether signals get thrown in the trash or shipped outside the cell, and this caused the immune activation.

How do these findings relate to Lowe Syndrome? The authors think these results suggest a possible cause for the seizures that patients experience. When similar immune-like cells in the brain release excessive inflammatory signals, it can cause several forms of epilepsy. Further, OCRL has been linked to at least one mouse model of epilepsy. Going forward, the researchers will try to identify which immune signals are responsible, and how these findings translate to human cells.

Del Signore SJ (*), Biber SA (*), Lehmann KS, Heimler SR, Rosenfeld BH, Eskin TL, Sweeney ST, Rodal AA. dOCRL maintains immune cell quiescence by regulating endosomal traffic. Plos Genet. 2017;13(10):e1007052.

 

 

Rosbash, Hall & Young Awarded Nobel Prize

Michael Rosbash, Nobel Laureate

Brandeis researchers Michael Rosbash, the Peter Gruber Endowed Chair in Neuroscience, and Professor Emeritus of Biology Jeffrey C. Hall have received this year’s Nobel Prize in Physiology or Medicine, together with Michael Young from The Rockefeller University,  for their pioneering work on the molecular mechanisms controlling circadian rhythm.

More about Michael

More about Jeff

More about Drosophila

 

Sebastian Kadener Returns to Brandeis as Associate Professor

Sebastian Kadener

From 2002 to 2008, Sebastian Kadener was a postdoc working in the Michael Rosbash laboratory. He is returning to Brandeis as an Associate Professor of Biology. Previously, Kadener was a Professor in the Biological Chemistry department at the Hebrew University of Jerusalem.

The Kadener laboratory studies how molecular processes in the brain determines behavior with a special emphasis on RNA metabolism. Additionally, they study the role of circular RNAs (circRNAs) at the molecular and neural levels as well as the mechanisms underlying circadian clocks.

Kadener’s paper, “Translation of CircRNAs”, appeared in Molecular Cell in April 2017. It was reviewed in Nature Reviews Genetics and Science Daily.

Garrity lab finds moisture-sensing genes in mosquitoes

Summary figure for Garrity lab paperby Zachary Knecht, PhD candidate

As the solvent of living cells, water is critical for all life on earth.  This makes monitoring how environmental conditions impact evaporation and subsequently sensing and locating water sources important for animal survival. This is particularly critical for insects, whose small body size makes them highly susceptible to dehydration. In addition, moisture sensing, or hygrosensation, is also important for the spread of insect-born disease. Mosquitoes that spread malaria or viruses like dengue and Zika, not only need to locate bodies of standing water in which to lay eggs, but also home in on the moisture that emanates from our bodies when searching for a blood meal. This dual role for hygrosensing in mosquito biology makes their hygrosensory machinery a promising target for pest control strategies. Until now though, the genes and molecules that function in insect hygrosensation have been completely unknown.

In a pair of recent papers in the journal eLife, researchers in the Garrity Lab at Brandeis University, in collaboration with colleagues at the University of Lausanne in Switzerland, have uncovered the cellular and molecular mechanisms that underlie insect hygrosensation using the fruit fly Drosophila melanogaster. Like mosquitoes, fruit flies detect humidity through specialized, innervated hair-like structures located on their antennae called sensilla. Each hygrosensing sensilla contains one cell that responds to increasing humidity (a moist cell), and one that responds to decreasing humidity (a dry cell).  These papers demonstrate that the balance of activity between dry and moist cells allows the insect to seek out or avoid particular humidity levels, a preference which changes depending on how hydrated or dehydrated the fly is.

To identify the molecules involved in sensing moisture, the researchers looked for mutant flies unable to distinguish between humid and dry air. They found that animals with mutations in four different genes disrupted the behavior. Strikingly, each of these genes encoded a different member of the same family of sensory receptors, the so-called Ionotropic Receptors or IRs.  Although IRs are found only in invertebrates, they belong to the same family as the ionotropic Glutamate Receptors, which lie at the heart of communication between nerve cells in the animal brain, including the human brain.  IRs differ from these relatives in that instead of sensing signals sent by neurons, they detect signals coming from the environment.  IRs are best known to act as chemical receptors, but the group found that a subset of IRs act instead to sense humidity. The researchers found two broadly expressed IRs, Ir25a and Ir93a, were required by both the dry cells and moist cells while the other two IRs, Ir40a and Ir68a, were specifically required by the dry and the moist cells, respectively. This suggests that Ir25a and Ir93a contribute to the formation of both moist and dry receptors, while Ir40a and Ir68a provide the dry- and moist-specific subunits to the receptor. Consistent with this view, the loss of either Ir68a or Ir40a alone only partially reduces the animal’s ability to sense humidity, but animals with mutations in Ir25a, Ir93a or both Ir40a and Ir68a are completely blind to moisture.

Having identified the specific genes required for sensing moisture, the next step is to determine the precise mechanism by which humidity activates these receptors. Furthermore, these genes are conserved in mosquitoes and other disease vectors, providing a clear path to translate what’s known about fly hygrosensation into the mosquito. These papers lay the groundwork for new mosquito control strategies that aim to precisely inhibit their ability to seek out water to reproduce and to seek out hosts to bite and spread deadly pathogens.

Leslie Griffith Receives SASTRA-Obaid Siddiqi Award

SASTRA award


Model depicts how the integration of light, ambient temperature, the circadian clock and homeostatic sleep drive sets the balance between daytime and nighttime sleep [Parisky, K.M., Agosto Rivera, J.L., Donelson, N.C., Kotecha, S. and Griffith, L.C. (2016) “Reorganization of sleep by temperature in Drosophila requires light, the homeostat and the circadian clock” Curr Biol 26:882-892]

Leslie C. Griffith, Nancy Lurie Marks Professor of Neuroscience and Director of the Volen National Center for Complex Systems, has received the SASTRA–Obaid Siddiqi Award for excellence in life sciences. The prize is given by the Shanmugha Arts, Science, Technology & Research Academy (SASTRA) University in Thanjavur, India. Siddiqi was a pioneering molecular biologist and founder of the Molecular Biology Unit of the Tata Institute for Fundamental Research.

Griffith’s interests range from the biochemistry of neuronal signal transduction, in particular the role of CaMKII in memory formation, to the hierarchical relationships between complex behaviors such as sleep and learning. She has contributed to our understanding of these issues using genetic approaches in Drosophila melanogaster and believes that model systems have an important place in pioneering the understanding of basic biological processes. Her lab has been active in developing tools that allow interrogation of molecular and cellular processes with temporal and spatial resolution in freely behaving animals to bridge the molecule-behavior gap.

Griffith received the award on February 28, 2017.

Neurons that make flies sleep

Sleep is known to be regulated by both intrinsic (what time is it?) and environmental factors (is it hot today?). How exactly these factors are integrated at the cellular level is a hot topic for investigation, given the prevalence of sleep disorders. Researchers in the Rosbash and Griffith labs are pursuing the question in the fruit fly Drosophila melanogaster, to take advantage of the genetic tools in the model system and the excellent understanding of circadian rhythms in the fly.

Like other animals, the fruit fly displays a robust activity/sleep pattern, which consists of a morning (M) activity peak, a middle-day siesta, an evening (E) activity peak and nighttime sleep. M and E peaks are controlled by different subgroups of circadian neurons such as wake-promoting M and E clock cells.

In a paper just published in Nature, Brandeis postdoctoral fellow Fang Guo and coworkers identify a small group of circadian neurons, a subset of the glutamatergic DN1 (gDN1s) cells, which have a critical role in both types of regulation. The authors manipulated the gDN1s activity by using recently developed optogenetics tools, and found activity of those neurons is both necessary and sufficient to promote sleep.

circadian-feedback

The cartoon model illustrates how the circadian neuron negative feedback set the timing of activity and siesta of Drosophila. The arousal-promoting M cells (sLNv) release pigment-dispersing factor (PDF) peptide to promote M activity at dawn. PDF peptide can activate gDN1s, which release glutamate to inhibit arousal-promoting M and E (LNds) cells and cause a middle-day siesta. At evening, the gDN1s activity is reduced to trough levels and release E cell activity from inhibition.

DN1s enhance baseline sleep by acting as feedback inhibitors of previously identified wake-promoting M and E clock cells, making them the first known sleep-promoting neurons in this circadian circuit. It is already known that M cell can activate gDN1s at dawn. Thus the daily activity-sleep pattern of Drosophila is timed by the circadian neuron negative feedback circuitry (see Figure).  More interestingly, by using in vivo calcium reporters, the authors reveal that the activity of the gDN1s is also shown to be sexually dimorphic, explaining the well-known difference in daytime sleep between males and females. DN1s also have a key role in mediating the effects of temperature on daytime sleep. The circadian and environmental responsiveness of gDN1s positions them to be key players in shaping sleep to the needs of the individual animal.

Authors on the paper include postdocs Guo, Junwei Yu and Weifei Luo, staff member Kate Abruzzi, and Brandeis graduate Hyung Jae Jung ’15 (Biology/HSSP).

Guo F, Yu J, Jung HJ, Abruzzi KC, Luo W, Griffith LC, Rosbash M. Circadian neuron feedback controls the Drosophila sleep-activity profile. Nature. 2016.

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