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Results for “Physiology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 127 records · Page 7Linked to original sources

bioRxiv2017

Bacterial Colonization Stimulates A Complex Physiological Response In The Immature Human Intestinal Epithelium

The human gastrointestinal tract is immature at birth, yet must adapt to dramatic changes such as oral nutrition and microbial colonization. The confluence of these factors can lead to severe inflammatory disease in premature infants; however, investigating complex environment-host interactions is diZcult due to limited access to immature human tissue. Here, we demonstrate that the epithelium of human pluripotent stem cell-derived human intestinal organoids is globally similar to the immature human epithelium and we utilize HIOs to investigate complex host-microbe interactions in this naive epithelium. Our findings demonstrate that the immature epithelium is intrinsically capable of establishing a stable host-microbe symbiosis. Microbial colonization leads to complex contact and hypoxia driven responses resulting in increased antimicrobial peptide production, maturation of the mucus layer, and improved barrier function. These studies lay the groundwork for an improved mechanistic understanding of how colonization influences development of the immature human intestine.

developmental biology↗

bioRxiv2017

Effects of Progesterone on the reproductive physiology in zebrafish

Recent studies have investigated that the synthetic progestins may lead to health issues to the aquatic organisms. Progesterone is a steroidal progestin and has been used as a contraceptive drug, which is detected in the aquatic ecosystem. However, the potential effects of progesterone on the fish reproduction are largely unclear. Here, we tested the effects of progesterone on the fish reproductive and endocrine systems. Adult zebrafish were exposed to progesterone for 10 days at environmental concentrations. The production of eggs was reduced in the exposed fish, and the circulating concentrations of estradiol (E2) and testosterone (T) in female fish or 11-keto testosterone (11-KT) in male fish were significantly diminished. Our results suggested that progesterone may cause adverse health effects on fish by disrupting the endocrine system, and short-term exposure to progesterone could overt affect the fish reproduction.

pharmacology and toxicology↗

bioRxiv2017

Three-dimensional plant architecture and sunlit-shaded dynamics: A stochastic model to enable high-throughput physiological analysis

Background and AimsDiurnal changes in solar position and intensity combined with the structural complexity of plant architecture result in highly variable and dynamic light patterns within the plant canopy. This affects productivity through the complex ways that photosynthesis responds to changes in light intensity. Current methods to characterise light dynamics, such as ray-tracing, are able to produce data with excellent spatio-temporal resolution but are computationally intensive and the resultant data are complex and high dimensional. This necessitates development of more economical models for summarising the data and for simulating realistic light patterns over the course of a day.\n\nMethodsHigh-resolution reconstructions of field-grown plants are assembled in various configurations to form canopies, and a forward ray-tracing algorithm is applied to the canopies to compute light dynamics at high (1 minute) temporal resolution. From the ray-tracer output, the sunlit or shaded state for each patch on the plants is determined, and these data are used to develop a novel stochastic model for the sunlit-shaded patterns. The model is designed to be straightforward to fit to data using maximum likelihood estimation, and fast to simulate from.\n\nKey ResultsFor a wide range of contrasting 3D canopies, the stochastic model is able to summarise, and replicate in simulations, key features of the light dynamics. When light patterns simulated from the stochastic model are used as input to a model of photoinhibition, the predicted reduction in carbon gain is similar to that from calculations based on the (extremely costly) ray-tracer data.\n\nConclusionsThe model provides a way to summarise highly complex data in a small number of parameters, and a cost-effective way to simulate realistic light patterns. Simulations from the model will be particularly useful for feeding into larger-scale photosynthesis models for calculating how light dynamics affects the photosynthetic productivity of canopies.

plant biology↗

bioRxiv2017

ATP sensing in living plant cells reveals tissue gradients and stress dynamics of energy physiology

Growth and development of plants is ultimately driven by light energy captured through photosynthesis. ATP acts as universal cellular energy cofactor fuelling all life processes, including gene expression, metabolism, and transport. Despite a mechanistic understanding of ATP biochemistry, ATP dynamics in the living plant have been largely elusive. Here we establish live MgATP2- assessment in plants using the fluorescent protein biosensor ATeam1.03-nD/nA. We generate Arabidopsis sensor lines and investigate the sensor in vitro under conditions appropriate for the plant cytosol. We establish an assay for ATP fluxes in isolated mitochondria, and demonstrate that the sensor responds rapidly and reliably to MgATP2- changes in planta. A MgATP2- map of the Arabidopsis seedling highlights different MgATP2- concentrations between tissues and in individual cell types, such as root hairs. Progression of hypoxia reveals substantial plasticity of ATP homeostasis in seedlings, demonstrating that ATP dynamics can be monitored in the living plant.\n\nOne-sentence SummarySensing of MgATP2- by fluorimetry and microscopy allows dissection of ATP fluxes of isolated organelles, and dynamics of cytosolic MgATP2- in vivo.\n\nFunding AgenciesThis work was supported by the Deutsche Forschungsgemeinschaft (DFG) through the Emmy-Noether programme (SCHW1719/1-1; M.S. and GR4251/1-1; C.G.), the Research Training Group GRK 2064 (M.S.; A.J.M.), the Priority Program SPP1710 (A.J.M.) and a grant (SCHW1719/5-1; M.S.) as part of the package PAK918. The Seed Fund grant CoSens from the Bioeconomy Science Center, NRW (A.J.M.; M.S.) is gratefully acknowledged. The scientific activities of the Bioeconomy Science Center were financially supported by the Ministry of Innovation, Science and Research within the framework of the NRW Strategieprojekt BioSC (No. 313/323-400-002 13). A.Co. received funding by the Ministero dellIstruzione, dellUniversita e della Ricerca through the FIRB 2010 programme (RBFR10S1LJ_001) and Piano di Sviluppo di Ateneo 2015 (Universita degli Studi di Milano). M.Z. received funding by the Ministero dellIstruzione, dellUniversita e della Ricerca (Italy) through the PRIN 2010 programme (PRIN2010CSJX4F). S.W. and T.N. received travel support by the Deutscher Akademischer Austauschdienst (DAAD). V.D.C. was supported by the European Social Fund, Operational Programme 2007/2013, and an Erasmus+ Traineeship grant. M.D.F was supported by The Human Frontier Science Program (RPG0053/2012), and the Leverhulme Foundation (RPG-2015-437). I.M.M. was supported by a grant from the Danish Council for Independent Research - Natural Sciences. V.C.P. was supported by the Innovation and Technology Fund (Funding Support to Partner State Key Laboratories in Hong Kong) of the HKSAR.\n\nAbbreviationsAAC - ADP/ATP carrier; AK - adenylate kinase; cAT - carboxyatractyloside; CCCP - carbonyl cyanide m-chlorophenyl hydrazone; CFP - cyan fluorescent protein; CLSM - confocal laser scanning microscopy; ETC - electron transport chain; FRET - Forster Resonance Energy Transfer; LSFM - light sheet fluorescence microscopy.

plant biology↗

bioRxiv2017

Ectopic activation of the Spindle Assembly Checkpoint reveals its biochemical design and physiological operation

Switch-like activation of the Spindle Assembly Checkpoint (SAC) is critical for accurate chromosome segregation during cell division. To determine the mechanisms that implement it, we engineered an ectopic, kinetochore-independent SAC activator, the \"eSAC\". The eSAC stimulates the SAC signaling cascade by artificially dimerizing the Mps1 kinase domain and a cytosolic KNL1 phosphodomain, the signaling scaffold in the kinetochore. Quantitative analyses and mathematical modeling of the eSAC reveal that the recruitment of multiple SAC proteins by the KNL1 phosphodomain stimulates synergistic signaling, which enables a small number of KNL1 molecules produce a disproportionately strong anaphase-inhibitory signal. However, when multiple KNL1 molecules signal concurrently, they compete for a limited cellular pool of SAC proteins. This frustrates synergistic signaling and modulates signal output. Together, these mechanisms institute automatic gain control - inverse, non-linear scaling between the signal output per kinetochore and the unattached kinetochore number, and thus enact the SAC switch.

cell biology↗

bioRxiv2017

Physiological and pathological brain activation in the anesthetized rat produces hemodynamic-dependent cortical temperature increases that can confound the BOLD fMRI signal.

Anesthetized rodent models are ubiquitous in pre-clinical neuroimaging studies. However, because the associated cerebral morphology and experimental methodology results in a profound negative brain-core temperature differential, cerebral temperature changes during functional activation are likely to be principally driven by local inflow of fresh, core-temperature, blood. This presents a confound to the interpretation of blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) data acquired from such models, since this signal is also critically temperature-dependent. Nevertheless, previous investigation on the subject is surprisingly sparse. Here, we address this issue through use of a novel multi-modal methodology in the urethane anesthetized rat. We reveal that sensory stimulation, hypercapnia and recurrent acute seizures induce significant increases in cortical temperature that are preferentially correlated to changes in total hemoglobin concentration, relative to cerebral blood flow and oxidative metabolism. Furthermore, using a phantom-based evaluation of the effect of such temperature changes on the BOLD fMRI signal, we demonstrate a robust inverse relationship between the two. These findings indicate that temperature increases, due to functional hyperemia, should be accounted for to ensure accurate interpretation of BOLD fMRI signals in pre-clinical neuroimaging studies.

neuroscience↗

bioRxiv2017

Microbiome-by-ethanol interactions impact Drosophila melanogaster fitness and physiology

Ethanol is one of the worlds most abused drugs yet the impacts of chronic ethanol consumption are debated. Ethanol is a prevalent component in the diets of diverse animals and can act as a nutritional source, behavior modulator, and a toxin. The source of ethanol is microbes, which can both produce and degrade ethanol, and the gut microbiome has been associated with differential health outcomes in chronic alcoholism. To disentangle the various and potentially interacting roles of bacteria and ethanol on host health, we developed a model for chronic ethanol ingestion in the adult fruit fly, Drosophila melanogaster, which naturally consumes a diet between 0 and 5% ethanol. We took advantage of the tractability of the fly microbiome, which can be experimentally removed to separate the direct and indirect effects of commensal microbes. We found that moderate to heavy ethanol ingestion decreased lifespan and reproduction, without causing inebriation. These effects were more pronounced in flies lacking a microbiome, but could not be explained by simple bacterial degradation of ethanol. However, moderate ethanol ingestion increased reproduction in bacterially-colonized flies, relative to bacteria-free flies. Ethanol decreased intestinal stem cell turnover in bacterially-colonized flies and decreased intestinal barrier failure and increased fat content in all flies, regardless of microbiome status. Analysis of host gene expression finds that ethanol triggers the innate immune response, but only in flies colonized with bacteria. Taken together we show that, chronic ethanol ingestion negatively impacts fly health in a microbiome-dependent manner.

microbiology↗

bioRxiv2017

Genome wide association study of behavioral, physiological and gene expression traits in a multigenerational mouse intercross

The LG/J x SM/J advanced intercross line of mice (LG x SM AIL) is a multigenerational outbred population. High minor allele frequencies, a simple genetic background, and the fully sequenced LG and SM genomes make it a powerful population for genome-wide association studies. Here we use 1,063 AIL mice to identify 126 significant associations for 50 traits relevant to human health and disease. We also identify thousands of cis- and trans-eQTLs in the hippocampus, striatum, and prefrontal cortex of [~]200 mice. We replicate an association between locomotor activity and Csmd1, which we identified in an earlier generation of this AIL, and show that Csmd1 mutant mice recapitulate the locomotor phenotype. Our results demonstrate the utility of the LG x SM AIL as a mapping population, identify numerous novel associations, and shed light on the genetic architecture of mammalian behavior.

genetics↗

bioRxiv2018

Apparent oxygen half saturation constant for nitrifiers: genus specific, inherent physiological property, or artefact of colony morphology?

We report that a single Nitrospira sublineage I OTU performs nitrite oxidation in several full-scale domestic wastewater treatment plants (WWTPs) in the tropics (29-31 {degrees}C). Contrary to the prevailing theory for the relationship between nitrite oxidizing bacteria (NOB) and ammonia oxidizing bacteria (AOB), members of the Nitrospira sublineage I OTU had an apparent half saturation coefficient, Ks(app) lower than that of the full-scale domestic activated sludge cohabitant AOB (0.09 {+/-} 0.02 g O2 m-3 versus 0.3 {+/-} 0.03 g O2 m-3). Paradoxically, NOB may thus thrive under conditions of low oxygen supply. Low dissolved oxygen (DO) conditions could enrich for and high aeration inhibit the NOB in a long-term lab-scale reactor. The relative abundance of Nitrospira gradually decreased with increasing DO until it was washed out. Nitritation was sustained even after the DO was lowered subsequently. Based on 3D-fluorescence in situ hybridization (FISH) image analysis, the morphologies of AOB and NOB microcolonies responded to DO levels in accordance with their apparent oxygen half saturation constant Ks(app). When exposed to the same oxygenation level, NOB formed densely packed spherical clusters with a low surface area-to-volume ratio compared to the Nitrosomonas-like AOB clusters, which maintained a porous and non-spherical morphology. Microcolony morphology is thus a way for AOB and NOB to regulate oxygen exposure and sustain the mutualistic interaction. However, short-term high DO exposure can select for AOB and against NOB in full-scale domestic WWTPs and such population dynamics depend on which specific AOB and NOB species predominate under given environmental conditions.

systems biology↗

bioRxiv2018

Visual physiology of the Layer 4 cortical circuit in silico

Despite advances in experimental techniques and accumulation of large datasets concerning the composition and properties of the cortex, quantitative modeling of cortical circuits under in-vivo-like conditions remains challenging. Here we report and publicly release a biophysically detailed circuit model of layer 4 in the mouse primary visual cortex, receiving thalamo-cortical visual inputs. The 45,000-neuron model was subjected to a battery of visual stimuli, and results were compared to published work and new in vivo experiments. Simulations reproduced a variety of observations, including effects of optogenetic perturbations. Critical to the agreement between responses in silico and in vivo were the rules of functional synaptic connectivity between neurons. Interestingly, after extreme simplification the model still performed satisfactorily on many measurements, although quantitative agreement with experiments suffered. These results emphasize the importance of functional rules of cortical wiring and enable a next generation of data-driven models of in vivo neural activity and computations.\n\nAUTHOR SUMMARYHow can we capture the incredible complexity of brain circuits in quantitative models, and what can such models teach us about mechanisms underlying brain activity? To answer these questions, we set out to build extensive, bio-realistic models of brain circuitry employing systematic datasets on brain structure and function. Here we report the first modeling results of this project, focusing on the layer 4 of the primary visual cortex (V1) of the mouse. Our simulations reproduced a variety of experimental observations in a large battery of visual stimuli. The results elucidated circuit mechanisms determining patters of neuronal activity in layer 4 - in particular, the roles of feedforward thalamic inputs and specific patterns of intracortical connectivity in producing tuning of neuronal responses to the orientation of motion. Simplification of neuronal models led to specific deficiencies in reproducing experimental data, giving insights into how biological details contribute to various aspects of brain activity. To enable future development of more sophisticated models, we make the software code, the model, and simulation results publicly available.

neuroscience↗

bioRxiv2018

STF-62247 blocks late stages of autophagy by disrupting lysosomal physiology

STF-62247 was previously identified as a promising compound able to selectively target the loss of the tumor suppressor gene von Hippel-Lindau (VHL) in renal cell carcinomas. This present work investigates the effect of STF-62247 on the autophagic flux. Our investigations show that STF-62247 blocks late stages of autophagy through lysosomal disruption. Indeed, STF-62247 localizes at lysosomes and causes unregulated swelling of these acidic compartments in VHL-mutated cells, linking a potential role for VHL in lysosomal integrity. Knock-outs of BECN1 and ATG5 were able to rescue the viability of VHL-mutated cells in response to STF-62247 but did not rescue the lysosomal swelling. In fact, neutralizing the lysosomal pH by inhibiting the vacuolar H+-ATPase completely rescued this phenotype. Moreover, we show that STF-62247 disrupts endocytic routes and causes cathepsin D trafficking defects. This mechanistic study is the first to characterize STF-62447 as a novel lysosomotropic compound. Importantly, our study re-classifies STF-62247 as a blocker of later stages of autophagy and highlights its potential usage as a powerful new tool for endocytic and autophagy-related research.

cancer biology↗

bioRxiv2018

Neuronal morphologies built for reliable physiology in a rhythmic motor circuit

The neurons of the crustacean stomatogastric ganglion (STG) exhibit highly-conserved firing patterns, voltage waveforms, and circuit functions despite quantifiable animal-to-animal variability in their neuronal morphologies. In recent work, we showed that one neuron type, the Gastric Mill (GM) neuron, is electrotonically compact and operates much like a single compartment, despite having thousands of branch points and a total cable length on the order of 10 mm. Here, we explore how STG neurite morphology shapes voltage signal propagation and summation in four STG neuron types. We use focal glutamate photo-uncaging in tandem with somatic intracellular recordings to examine passive electrotonic structure and voltage signal summation in the GM neuron and three additional STG neuron types: Lateral Pyloric (LP), Ventricular Dilator (VD), and Pyloric Dilator (PD) neurons. In each neuron, we measured the amplitudes and apparent reversal potentials (Erevs) of inhibitory responses evoked with focal glutamate photo-uncaging at more than 20 sites varying in their distance (100-800 m) from the somatic recording site in the presence of TTX. Apparent Erevs were relatively invariant (mean CVs = 0.04, 0.06, 0.05, and 0.08 for 5-6 GM, LP, PD, VD neurons, respectively), suggesting that all four neuron types are similarly electrotonically uniform and compact. We then characterized the directional sensitivity and arithmetic of voltage summation (with fast sequential activation of 4-6 sites) in individual STG neurites. All four neuron types showed no directional bias in voltage signal summation and linear voltage summation. We motivate these experiments with a proof-of-concept computational model that suggests the immense tapering of STG neurite diameters: from 10-20 m to sub-micron diameters at the terminal tips, may explain the uniform electrotonic structures experimentally observed and contribute to the robust nature of this central pattern-generating circuit.

neuroscience↗

bioRxiv2018

A physiological drop in pH decreases mitochondrial respiration, and AMPK and Akt signalling, in L6 myocytes

Exercise stimulates mitochondrial biogenesis and increases mitochondrial respiratory function and content. However, during high-intensity exercise muscle pH can decrease below pH 6.8 with a concomitant increase in lactate concentration. This drop in muscle pH is associated with reduced exercise-induced mitochondrial biogenesis, whilst increased lactate may act as a signaling molecule to affect mitochondrial biogenesis. Therefore, in this study we wished to determine the impact of altering pH and lactate concentration in L6 myotubes on genes and proteins known to be involved in mitochondrial biogenesis. We also examined mitochondrial respiration in response to these perturbations. Differentiated L6 myotubes were exposed to normal (pH 7.5), low (pH 7.0) or high pH (pH 8.0) media with and without 20 mM sodium L-lactate for 1 and 6 h. Low pH and 20 mM Sodium L-Lactate resulted in decreased Akt (Ser473) and AMPK (T172) phosphorylation at 1 h compared to controls, whilst at 6 h the nuclear localisation of HDAC5 was decreased. When the pH was increased both Akt (Ser473) and AMPK (T172) phosphorylation was increased at 1 h. Overall increased lactate decreased the nuclear content of HDAC5 at 6 h. Exposure to both high and low pH media significantly decreased basal mitochondrial respiration, ATP turnover, and maximum mitochondrial respiratory capacity. These data indicate that muscle pH affects several metabolic signalling pathways, including those required for mitochondrial function.

cell biology↗

bioRxiv2018

Sensing Plant Physiology and Environmental Stress by Automatically Tracking Fj and Fi Features in PSII Chlorophyll Fluorescence Induction

Following a step excitation, chlorophyll fluorescence (ChlF) from photosystem II of a dark-adapted plant leaf exhibits the well-known OJIP pattern. The OJIP induction has been widely applied in plant science, agriculture engineering, and environmental engineering. While the J and I phases are related to transitions of photochemical reaction redox states, characteristic fluorescence intensities for the two phases (Fj and Fi) are often treated as fixed time points in routine measurement and thus do not account for variations in plant and experimental conditions, which (1) neglects the time differences, potentially useful information for characterizing plant status and environmental factors, and (2) leads to errors in measured Fj and Fi values. In this work, a method for consistent measurement of Fj and Fi was developed through polynomial fitting and curvature analysis. The method measures the curvatures in the OJIP curve and automatically tracks the characteristic transition points under variable sample and experimental conditions. Experiments were carried out to demonstrate the concept and classification capabilities of the developed method. This research established a new framework to analyze ChlF and enhanced the applications of ChlF.

plant biology↗

bioRxiv2018

Novel cytonuclear combinations modify Arabidopsis seed physiology and vigor

The influence of intraspecific variation in cytoplasmic genomes and cytonuclear interactions on key seed traits that can impact adaptation and agriculture has not been thoroughly explored, so far. Here, dormancy, germination performance and longevity of seeds have been assessed in Arabidopsis plants with novel cytonuclear combinations that disrupt coadaptation between natural variants of nuclear and cytoplasmic genomes. Although all three traits were affected by cytonuclear reshuffling, the sensitivity of seed traits to cytoplasmic change was dependent on the nuclear background. Both deleterious and, more surprisingly, favorable effects of novel cytonuclear combinations (in comparison with the nuclear parent) were observed, suggesting suboptimal genetic combinations exist in natural populations for these traits. Significant changes on dormancy and germination performance due to specific cytonuclear interacting combinations mainly occurred in opposite directions, in accordance with the previously proposed dormancy continuum. Consistently, reduced sensitivity to exogenous ABA and faster endogenous ABA decay during germination were observed in a novel cytonuclear combination that also exhibited enhanced longevity and better germination performance, compared to its natural nuclear parent. Cytoplasmic genomes, therefore, represent an additional resource of natural variation for breeding seed vigor traits.\n\nIssue sectionGrowth and development\n\nHighlightNatural variation in Arabidopsis organelles and cytonuclear interactions influence seed dormancy, longevity and germination performance. Enhanced seed vigor was obtained through the creation of novel cytonuclear combinations.

plant biology↗

bioRxiv2018

A multi-scale model reveals cellular and physiological mechanisms underlying hyperpolarisation-gated synaptic plasticity

Neurons in the medial vestibular nucleus (MVN) display hyperpolarisation-gated synaptic plasticity, where inhibition believed to come from cerebellar cortical Purkinje cells can induce long-term potentiation (LTP) or long-term depression (LTD) of vestibular nerve afferent synapses. This phenomenon is thought to underlie the plasticity of the vestibulo-ocular reflex (VOR). The molecular and cellular mechanisms involved are largely unknown. Here we present a novel multi-scale computational model, which captures both electrophysiological and biochemical signalling at vestibular nerve synapses on proximal dendrites of the MVN neuron. We show that AMPA receptor phosphorylation at the vestibular synapse depends in complex ways on dendritic calcium influx, which is in turn shaped by patterns of post-synaptic hyperpolarisation and vestibular nerve stimulation. Hyperpolarisation-gated synaptic plasticity critically depends on the activation of LVA calcium channels and on the interplay between CaMKII and PP2B in dendrites of the post-synaptic MVN cell. The extent and direction of synaptic plasticity depend on the strength and duration of hyperpolarisation, and on the relative timing of hyperpolarisation and vestibular nerve stimulation. The multi-scale model thus enables us to explore in detail the interactions between electrophysiological activation and post-synaptic biochemical reaction systems. More generally, this model has the potential to address a wide range of questions about neural signal integration, post-synaptic biochemical reaction systems and plasticity.

neuroscience↗

bioRxiv2018

Multi-lab EcoFAB study shows highly reproducible physiology and depletion of soil metabolites by a model grass

O_LIThere is a dynamic reciprocity between plants and their environment: On one hand, the physiochemical properties of soil influence plant morphology and metabolism, while on the other, root morphology and exudates shape the environment surrounding roots. Here, we investigate both of these aspects as well as the reproducibility of these responses across laboratories.\nC_LIO_LIThe model grass Brachypodium distachyon was grown in phosphate-sufficient and phosphate-deficient mineral media, as well as in sterile soil extract, within fabricated ecosystem (EcoFAB) devices across four laboratories.\nC_LIO_LITissue weight and phosphate content, total root length, root tissue and exudate metabolic profiles were found to be consistent across laboratories and distinct between experimental treatments. Plants grown in soil extract were morphologically and metabolically distinct in all laboratories, with root hairs four times longer compared to other growth conditions. Further, plants depleted half of the investigated metabolites from the soil extract.\nC_LIO_LITo interact with their environment, plants not only adapt morphology and release complex metabolite mixtures; they also selectively deplete a range of soil-derived metabolites. The EcoFABs utilized here generated high inter-laboratory reproducibility, demonstrating that their value in standardized investigations of plant traits.\nC_LI

plant biology↗

bioRxiv2018

Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

Genes implicated in autism spectrum disorder (ASD) are enriched with chromatin regulators, but the mechanisms leading to the abnormal behavior and cognition are still unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior. We generated conditional knockout mice with brain-specific mutation in Pogz, a heterochromatin regulator recurrently mutated in ASD and other neurodevelopmental disorders, and demonstrated that these mice display phenotypes that resemble the human condition. Pogz deficiency led to smaller brain, growth impairment, motor learning deficits, and increased social interactions that mimic the human overly friendly phenotype. At the molecular level, reporter assay indicated that POGZ functions as a negative regulator of transcription through its interaction with HP1 proteins. In accordance, we found a significant upregulation of gene expression, most notably in the cerebellum. Furthermore, Pogz deficiency was associated with a significant reduction in the firing frequency of simple and complex spikes in cerebellar Purkinje cells with no changes in their intrinsic properties. Overall, our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and to motor and social abnormalities in ASD.

neuroscience↗