Zimmer M (2009) Chem Soc Rev "GFP: from jellyfish to the Nobel prize and beyond."

Zimmer M

[Chem Soc Rev, 2009]

On December 10, 2008 Osamu Shimomura, Martin Chalfie and Roger Tsien were awarded the Nobel Prize in Chemistry for "the discovery and development of the green fluorescent protein, GFP". The path taken by this jellyfish protein to become one of the most useful tools in modern science and medicine is described. Osamu Shimomura painstakingly isolated GFP from hundreds of thousands of jellyfish, characterized the chromophore and elucidated the mechanism of Aequorean bioluminescence. Martin Chalfie expressed the protein in E. coli and C. elegans, and Roger Tsien developed a palette of fluorescent proteins that could be used in a myriad of applications.

Zimmer M et al. (2009) Neuron "Neurons detect increases and decreases in oxygen levels using distinct guanylate cyclases."

Bargmann CI, Chronis N, Hudson ML, Chang AJ, Morton DB, Karow DS, Marletta MA, Pokala N, Zimmer M, Gray JM

[Neuron, 2009]

Homeostatic sensory systems detect small deviations in temperature, water balance, pH, and energy needs to regulate adaptive behavior and physiology. In C. elegans, a homeostatic preference for intermediate oxygen (O2) levels requires cGMP signaling through soluble guanylate cyclases (sGCs), proteins that bind gases through an associated heme group. Here we use behavioral analysis, functional imaging, and genetics to show that reciprocal changes in O2 levels are encoded by sensory neurons that express alternative sets of sGCs. URX sensory neurons are activated by increases in O2 levels, and require the sGCs gcy-35 and gcy-36. BAG sensory neurons are activated by decreases in O2 levels, and require the sGCs gcy-31 and gcy-33. The sGCs are instructive O2 sensors, as forced expression of URX sGC genes causes BAG neurons to detect O2 increases. Both sGC expression and cell-intrinsic dynamics contribute to the differential roles of URX and BAG in O2-dependent behaviors.

Prevedel R et al. (2014) Nat Methods "Simultaneous whole-animal 3D imaging of neuronal activity using light-field microscopy."

Kato S, Yoon YG, Boyden ES, Raskar R, Prevedel R, Schrodel T, Zimmer M, Pak N, Vaziri A, Hoffmann M, Wetzstein G

[Nat Methods, 2014]

High-speed, large-scale three-dimensional (3D) imaging of neuronal activity poses a major challenge in neuroscience. Here we demonstrate simultaneous functional imaging of neuronal activity at single-neuron resolution in an entire Caenorhabditis elegans and in larval zebrafish brain. Our technique captures the dynamics of spiking neurons in volumes of 700 m x 700 m x 200 m at 20 Hz. Its simplicity makes it an attractive tool for high-speed volumetric calcium imaging.

Lev I et al. (2022) Curr Biol "Predator-prey interactions: Strategic biting."

Lev I, Zimmer M

[Curr Biol, 2022]

The nematode Pristionchus pacificus occasionally encounters other nematode species that compete for similar resources. A new study shows that P. pacificus perform an aggressive patrolling and biting behavior to expel adult Caenorhabditis elegans nematodes from food patches.

Kaplan HS et al. (2018) Neuron "Sensorimotor Integration for Decision Making: How the Worm Steers."

Zimmer M, Kaplan HS

[Neuron, 2018]

Animals' movements actively shape their perception and subsequent decision making. In this issue of Neuron, Liu etal. (2018) show how C.elegans nematodes steer toward an odorant: a dedicated interneuron class integrates oscillatory olfactory signals, generated by head swings, with corollary discharge motor signals.

Wypijewska A et al. (2012) Biochemistry "7-methylguanosine diphosphate (m(7)GDP) is not hydrolyzed but strongly bound by decapping scavenger (DcpS) enzymes and potently inhibits their activity."

Wypijewska A, Darzynkiewicz E, Davis RE, Jemielity J, Bojarska E, Lukaszewicz M, Stepinski J

[Biochemistry, 2012]

Decapping scavenger (DcpS) enzymes catalyze the cleavage of a residual cap structure following 3' 5' mRNA decay. Some previous studies suggested that both m(7)GpppG and m(7)GDP were substrates for DcpS hydrolysis. Herein, we show that mononucleoside diphosphates, m(7)GDP (7-methylguanosine diphosphate) and m(3)(2,2,7)GDP (2,2,7-trimethylguanosine diphosphate), resulting from mRNA decapping by the Dcp1/2 complex in the 5' 3' mRNA decay, are not degraded by recombinant DcpS proteins (human, nematode, and yeast). Furthermore, whereas mononucleoside diphosphates (m(7)GDP and m(3)(2,2,7)GDP) are not hydrolyzed by DcpS, mononucleoside triphosphates (m(7)GTP and m(3)(2,2,7)GTP) are, demonstrating the importance of a triphosphate chain for DcpS hydrolytic activity. m(7)GTP and m(3)(2,2,7)GTP are cleaved at a slower rate than their corresponding dinucleotides (m(7)GpppG and m(3)(2,2,7)GpppG, respectively), indicating an involvement of the second nucleoside for efficient DcpS-mediated digestion. Although DcpS enzymes cannot hydrolyze m(7)GDP, they have a high binding affinity for m(7)GDP and m(7)GDP potently inhibits DcpS hydrolysis of m(7)GpppG, suggesting that m(7)GDP may function as an efficient DcpS inhibitor. Our data have important implications for the regulatory role of m(7)GDP in mRNA metabolic pathways due to its possible interactions with different cap-binding proteins, such as DcpS or eIF4E.

O'Connell EM et al. (2015) J Infect Dis "Targeting Filarial Abl-like Kinases: Orally Available, Food and Drug Administration-Approved Tyrosine Kinase Inhibitors Are Microfilaricidal and Macrofilaricidal."

Nutman TB, O'Connell EM, Bennuru S, Steel C, Dolan MA

[J Infect Dis, 2015]

BACKGROUND: Elimination of onchocerciasis and lymphatic filariasis is targeted for 2020. Given the coincident Loa loa infections in Central Africa and the potential for drug resistance development, the need for new microfilaricides and macrofilaricides has never been greater. With the genomes of L. loa, Onchocerca volvulus, Wuchereria bancrofti, and Brugia malayi available, new drug targets have been identified. METHODS: The effects of the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib on B. malayi adult males, adult females, L3 larvae, and microfilariae were assessed using a wide dose range (0-100 M) in vitro. RESULTS: For microfilariae, median inhibitory concentrations (IC50 values) on day 6 were 6.06 M for imatinib, 3.72 M for dasatinib, and 81.35 M for nilotinib; for L3 larvae, 11.27 M, 13.64 M, and 70.98 M, respectively; for adult males, 41.6 M, 3.87 M, and 68.22 M, respectively; and for adult females, 42.89 M, 9.8 M, and >100 M, respectively. Three-dimensional modeling suggests how these tyrosine kinase inhibitors bind and inhibit filarial protein activity. CONCLUSIONS: Given the safety of imatinib in humans, plans are underway for pilot clinical trials to assess its efficacy in patients with filarial infections.

Emmons SW et al. (2021) Genetics "Methods for analyzing neuronal structure and activity in Caenorhabditis elegans."

Yemini E, Emmons SW, Zimmer M

[Genetics, 2021]

The model research animal Caenorhabditis elegans has unique properties making it particularly advantageous for studies of the nervous system. The nervous system is composed of a stereotyped complement of neurons connected in a consistent manner. Here, we describe methods for studying nervous system structure and function. The transparency of the animal makes it possible to visualize and identify neurons in living animals with fluorescent probes. These methods have been recently enhanced for the efficient use of neuron-specific reporter genes. Because of its simple structure, for a number of years, C. elegans has been at the forefront of connectomic studies defining synaptic connectivity by electron microscopy. This field is burgeoning with new, more powerful techniques, and recommended up-to-date methods are here described that encourage the possibility of new work in C. elegans. Fluorescent probes for single synapses and synaptic connections have allowed verification of the EM reconstructions and for experimental approaches to synapse formation. Advances in microscopy and in fluorescent reporters sensitive to Ca2+ levels have opened the way to observing activity within single neurons across the entire nervous system.

Fieseler C et al. (2020) J R Soc Interface "Unsupervised learning of control signals and their encodings in Caenorhabditis elegans whole-brain recordings."

Zimmer M, Fieseler C, Kutz JN

[J R Soc Interface, 2020]

A major goal of computational neuroscience is to understand the relationship between synapse-level structure and network-level functionality. <i>Caenorhabditis elegans</i> is a model organism to probe this relationship due to the historic availability of the synaptic structure (connectome) and recent advances in whole brain calcium imaging techniques. Recent work has applied the concept of network controllability to neuronal networks, discovering some neurons that are able to drive the network to a certain state. However, previous work uses a linear model of the network dynamics, and it is unclear if the real neuronal network conforms to this assumption. Here, we propose a method to build a global, low-dimensional model of the dynamics, whereby an underlying global linear dynamical system is actuated by temporally sparse control signals. A key novelty of this method is discovering candidate control signals that the network uses to control itself. We analyse these control signals in two ways, showing they are interpretable and biologically plausible. First, these control signals are associated with transitions between behaviours, which were previously annotated via expert-generated features. Second, these signals can be predicted both from neurons previously implicated in behavioural transitions but also additional neurons previously unassociated with these behaviours. The proposed mathematical framework is generic and can be generalized to other neurosensory systems, potentially revealing transitions and their encodings in a completely unsupervised way.

Skora S et al. (2018) Cell Rep "Energy Scarcity Promotes a Brain-wide Sleep State Modulated by Insulin Signaling in C.elegans."

Zimmer M, Skora S, Mende F

[Cell Rep, 2018]

Neural information processing entails a high energetic cost, but its maintenance is crucial for animal survival. However, the brain's energy conservation strategies are incompletely understood. Employing functional brain-wide imaging and quantitative behavioral assays, we describe a neuronal strategy in Caenorhabditis elegans that balances energy availability and expenditure. Upon acute food deprivation, animals exhibit a transiently elevated state of arousal, indicated by foraging behaviors and increased responsiveness to food-related cues. In contrast, long-term starvation suppresses these behaviors and biases animals to intermittent sleep episodes. Brain-wide neuronal population dynamics, which are likely energetically costly but important for behavior, are robust to starvation while animals are awake. However, during starvation-induced sleep, brain dynamics are systemically downregulated. Neuromodulation via insulin-like signaling is required to transiently maintain the animals' arousal state upon acute food deprivation. Our data suggest that the regulation of sleep and wakefulness supports optimal energy allocation.