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Biology subjects

Ikeda, M.

Publications and source records attributed to Ikeda, M..

24 records · Page 2Linked to original sources

Epigenetic regulation of a mouse PPARγ splicing variant, Pparγ1sv, during adipogenesis in 3T3-L1 cells

We have previously reported the abundant and ubiquitous expression of a newly identified splicing variant of mouse peroxisome proliferator-activated receptor-{gamma} (Ppar{gamma}), namely Ppar{gamma}1sv that encodes PPAR{gamma}1 protein, and plays an important role in adipogenesis. Ppar{gamma}1sv has a unique 5UTR sequence, compared to those of mouse Ppar{gamma}1 and Ppar{gamma}2 mRNAs. This implies the presence of a novel transcriptional initiation site and promoter for Ppar{gamma}1sv. We found that DNA methylation of 42 CpG sites in the proximal promoter region (-733 to -76) of Ppar{gamma}1sv was largely unchanged five days after adipocyte differentiation, whereas chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) using antibodies against H3K4me3 and H3K27ac revealed that these modifications significantly elevated at the transcription start sites of Ppar{gamma}1sv and Ppar{gamma}2 after differentiation.

cell biology↗

Presynaptic MAST Kinase Controls Bidirectional Post-SynapticResponses to Convey Stimulus Valence in C. elegans

Presynaptic plasticity is known to modulate the strength of synaptic transmission. However, it remains unknown whether regulation in presynaptic neurons alters the directionality -positive or negative-of postsynaptic responses. We report here that the C. elegans homologs of MAST kinase, Stomatin and Diacylglycerol kinase act in a thermosensory neuron to elicit in its postsynaptic neuron an excitatory or inhibitory response that correlates with the valence of thermal stimuli. By monitoring neural activity of the valence-coding interneuron in freely behaving animals, we show that the alteration between excitatory and inhibitory responses of the interneuron is mediated by controlling the balance of two opposing signals released from the presynaptic neuron. These alternative transmissions further generate opposing behavioral outputs necessary for the navigation on thermal gradients. Our findings reveal the previously unrecognized capability of presynaptic regulation to evoke bidirectional postsynaptic responses and suggest a molecular mechanism of determining stimulus valence.

neuroscience↗

Two pathways of p27Kip1 degradation are required for murine lymphoma driven by Myc and EBV latent membrane protein 2A

Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A), expressed in EBV latency, contributes to Burkitt Lymphoma (BL) development in a murine model by acting as a constitutively active B cell receptor (BCR) mimic. Mice expressing both LMP2A and MYC transgenes (LMP2A/{lambda}-MYC) develop tumors significantly faster than mice only expressing MYC ({lambda}-MYC). Previously, we demonstrated the cell cycle inhibitor p27Kip1 is present at significantly lower levels in LMP2A/{lambda}-MYC mice due to increased post-translational degradation. P27Kip1 degradation can occur in the cytoplasm following phosphorylation on serine 10 (S10), or in the nucleus via the SCFSkp2 complex, which depends on Cks1. We previously demonstrated a S10A knock-in of p27Kip1 (p27S10A/S10A), which prevented S10 phosphorylation, failed to significantly delay tumor onset in LMP2A/{lambda}-MYC mice. We also previously demonstrated that a Cks1 knockout partially delayed tumor onset in LMP2A/{lambda}-MYC mice, but onset was still significantly faster than in {lambda}-MYC mice. Here, we have combined both genetic manipulations in what we call p27Super mice. LMP2A/{lambda}-MYC/p27Super mice and {lambda}-MYC/p27Super mice both displayed dramatic delays in tumor onset. Strikingly, tumor development in LMP2A/{lambda}-MYC/p27Super mice was later than in {lambda}-MYC mice and not significantly different from {lambda}-MYC/p27Super mice. The p27Super genotype also normalized G1-S phase cell cycle progression, spleen size, and splenic architecture in LMP2A/{lambda}-MYC mice. Our results reveal both major pathways of p27Kip1 degradation are required for the accelerated BL development driven by LMP2A in our BL model and that blocking both degradation pathways is sufficient to delay Myc-driven tumor development with or without LMP2A.\n\nImportanceBurkitt lymphoma (BL) is a cancer that primarily affects children. The side effects of chemotherapy highlight the need for better BL treatments. Many BL tumors contain Epstein-Barr virus (EBV) and our goal is to determine what makes EBV-positive BL different from EBV-negative BL. This may lead to more specific treatments for both types. All cases of BL require overexpression of MYC. Mice engineered to express an EBV LMP2A along with MYC (LMP2A/{lambda}-MYC mice) develop tumors much more quickly than mice only expressing MYC ({lambda}-MYC mice). Blocking degradation of the cell cycle inhibitor protein p27Kip1 in LMP2A/{lambda}-MYC mice causes tumors to develop later than in {lambda}-MYC mice, showing that p27Kip1 degradation may play a larger role in EBV-positive BL than EBV-negative. Furthermore, our studies suggest the cell cycle may be an attractive target as a treatment option for LMP2A positive cancers in humans.

microbiology↗

Comparative genetic architectures of schizophrenia in East Asian and European populations

Author summarySchizophrenia is a severe psychiatric disorder with a lifetime risk of about 1% world-wide. Most large schizophrenia genetic studies have studied people of primarily European ancestry, potentially missing important biological insights. Here we present a study of East Asian participants (22,778 schizophrenia cases and 35,362 controls), identifying 21 genome-wide significant schizophrenia associations in 19 genetic loci. Over the genome, the common genetic variants that confer risk for schizophrenia have highly similar effects in those of East Asian and European ancestry (rg=0.98), indicating for the first time that the genetic basis of schizophrenia and its biology are broadly shared across these world populations. A fixed-effect meta-analysis including individuals from East Asian and European ancestries revealed 208 genome-wide significant schizophrenia associations in 176 genetic loci (53 novel). Trans-ancestry fine-mapping more precisely isolated schizophrenia causal alleles in 70% of these loci. Despite consistent genetic effects across populations, polygenic risk models trained in one population have reduced performance in the other, highlighting the importance of including all major ancestral groups with sufficient sample size to ensure the findings have maximum relevance for all populations.

genetics↗

Circuit Degeneracy Facilitates Robustness and Flexibility of Navigation Behavior in C. elegans

Animal behaviors are robust and flexible. To elucidate how these two conflicting features of behavior are encoded in the nervous system, we analyzed the neural circuits generating a C. elegans thermotaxis behavior, in which animals migrate toward the past cultivation temperature (Tc). We identified multiple circuits that are highly overlapping but individually regulate distinct behavioral components to achieve thermotaxis. When the regulation of a behavioral component is disrupted following single cell ablations, the other components compensate the deficit, enabling the animals to robustly migrate toward the Tc. Depending on whether the environmental temperature surrounding the animals is above or below the Tc, different circuits regulate the same behavioral components, mediating the flexible switch between migration up or down toward the Tc. These context-dependencies within the overlapping sub-circuits reveal the implementation of degeneracy in the nervous system, providing a circuit-level basis for the robustness and flexibility of behavior.

neuroscience↗

Identification Of Animal Behavioral Strategy By Inverse Reinforcement Learning ~ Its Application To Thermotaxis In C. elegans ~

Animals are able to reach a desired state in an environment by controlling various behavioral patterns. Identification of the behavioral strategy used for this control is important for understanding animals decision-making and is fundamental to dissect information processing done by the nervous system. However, methods for quantifying such behavioral strategies have not been fully established. In this study, we developed an inverse reinforcement-learning (IRL) framework to identify an animals behavioral strategy from behavioral time-series data. As a particular target, we applied this framework to C. elegans thermotactic behavior; after cultivation at a constant temperature with or without food, the fed and starved worms prefer and avoid from the cultivation temperature on a thermal gradient, respectively. Our IRL approach revealed that the fed worms used both absolute and temporal derivative of temperature and that their strategy comprised mixture of two strategies: directed migration (DM) and isothermal migration (IM). The DM is a strategy that the worms efficiently reach to specific temperature, which explained thermotactic behaviors of the fed worms. The IM is a strategy that the worms track along a constant temperature, which reflects isothermal tracking well observed in previous studies. We also showed the neural basis underlying the strategies, by applying our method to thermosensory neuron-deficient worms. In contrast to fed animals, the strategy of starved animals indicated that they escaped the cultivation temperature using only absolute, but not temporal derivative of temperature. Thus, our IRL-based approach is capable of identifying animal strategies from behavioral time-series data and will be applicable to wide range of behavioral studies, including decision-making of other organisms.\n\nAuthor SummaryUnderstanding animal decision-making has been a fundamental problem in neuroscience and behavioral ecology. Many studies analyze actions that represent decision-making in behavioral tasks, in which rewards are artificially designed with specific objectives. However, it is impossible to extend this artificially designed experiment to a natural environment, because in a natural environment, the rewards for freely-behaving animals cannot be clearly defined. To this end, we must reverse the current paradigm so that rewards are identified from behavioral data. Here, we propose a new reverse-engineering approach (inverse reinforcement learning) that can estimate a behavioral strategy from time-series data of freely-behaving animals. By applying this technique with thermotaxis in C. elegans, we successfully identified the reward-based behavioral strategy.

neuroscience↗