Biology subjects

Seguin, A.

Publications and source records attributed to Seguin, A..

10 recordsLinked to original sources

bioRxiv2026

THE MULTIFUNCTIONAL PROTEIN E4F1 REGULATES MELANOCYTIC FUNCTIONS IN MICE THROUGH PROTEIN TRANSLATION AND MITF EXPRESSION

The multifunctional protein E4 transcription factor 1 (E4F1) is an essential regulator of skin homeostasis, playing a critical role in epidermal stem cell maintenance and keratinocyte differentiation. However, the functions of E4F1 in other skin cell type remain poorly investigated. Here, we describe its role in melanogenesis, the physiological process for synthesis of melanin pigments. Using genetically engineered mouse models that enabled conditional inactivation of E4f1 specifically in melanocytes, we demonstrated that E4f1 loss induces severe pigmentation defects without affecting melanocyte survival nor differentiation. At the molecular level, E4f1 depletion reduces the expression of its direct transcriptional target genes involved in protein translation, including Elp3 and Eef1g, leading to translation alterations and consequently the induction of the Integrated Stress Response (ISR). This response resulted in microphthalmia-associated transcription factor (MITF) downregulation, inducing a decrease in the expression of enzymes involved in melanin synthesis. Consistent with these findings, Elp3 or Eef1g depletion recapitulated the decrease in MITF levels in vitro, and pharmacological inhibition of ISR partially rescued melanin content in vivo, confirming a key role of the E4F1-protein translation-ISR cascade in melanogenesis. Together, our data identify E4F1-associated translation functions as a key regulator of the melanocytic lineage.

physiology↗

bioRxiv2026

DNA double-strand break signaling induces aberrant neuronal activity

Aberrant neuronal activity is an early pathological feature of numerous neurodegenerative disorders, including tauopathy, and is thought to play a role in disease progression. However, the mechanism underlying abnormal neuronal activity remains elusive. Here, we reveal a relationship between DNA double-strand break (DSB)/p53 pathway activation and aberrant neuronal activity. Activating p53 as part of the DNA damage response via DSB induction, or by preventing MDM2-mediated p53 degradation, causes aberrant activity in both mouse and human neurons. p53 activation induces the expression of genes regulating synaptic transmission, and p53-responsive gene upregulation is overrepresented in postmortem human Alzheimers disease neurons burdened with neurofibrillary tangles (NFTs). Using a human iPSC-based cerebral organoid model of frontotemporal dementia that exhibits relevant pathologies including elevated DSBs, aberrant neuronal activity, and NFTs, we show that inhibiting p53 transcriptional activity with a small molecule ameliorates aberrant calcium fluctuations in neurons. Together, our findings highlight p53 inhibition as a novel therapeutic strategy to counter aberrant neuronal activity in neurodegenerative diseases characterized by tauopathy.

neuroscience↗

bioRxiv2024

The role of cholinergic signaling in multi-sensory gamma stimulation induced perivascular clearance of amyloid

Modulatory neurotransmitters exert powerful control over neurons and the brain vasculature. Gamma Entrainment Using Sensory Stimuli (GENUS) promotes amyloid clearance via increased perivascular cerebral spinal fluid (CSF) flux in mouse models of Alzheimers Disease. Here we use whole-brain activity mapping to identify the cholinergic basal forebrain as a key region responding to GENUS. In line with this, GENUS promoted cortical acetylcholine release, vascular dilation, vasomotion and perivascular clearance. Inhibiting cholinergic signaling abolished the effects of GENUS, including the promotion of arterial pulsatility, periarterial CSF influx, and the reduction of cortical amyloid levels. Our findings establish cholinergic signaling as an essential component of the brains ability to promote perivascular amyloid clearance via non-invasive sensory stimulation.

neuroscience↗

bioRxiv2023

Large genetic analysis of alcohol resistance and tolerance reveals an inverse correlation and suggests "true" tolerance mutants.

Tolerance occurs when, following an initial experience with a substance, more of the substance is required subsequently to induce the same behavioral effects. Tolerance is historically not well-understood, and numerous researchers have turned to model organisms, particularly Drosophila melanogaster, to unravel its mechanisms. Flies have high translational relevance for human alcohol responses, and there is substantial overlap in disease-causing genes between flies and humans, including those associated with Alcohol Use Disorder. Numerous Drosophila tolerance mutants have been described; however, approaches used to identify and characterize these mutants have varied across time and between labs and have mostly disregarded any impact of initial resistance/sensitivity to ethanol on subsequent tolerance development. Here, we have analyzed a large amount of data - our own published and unpublished data and data published by other labs - to uncover an inverse correlation between initial ethanol resistance and tolerance phenotypes. This inverse correlation suggests that initial resistance phenotypes can explain many perceived tolerance phenotypes. Additionally, we show that tolerance should be measured as a relative increase in time to sedation between an initial and second exposure rather than an absolute change in time to sedation. Finally, based on our analysis, we provide a method for using a linear regression equation to assess the residuals of potential tolerance mutants. We show that these residuals provide predictive insight into the likelihood of a mutant being a true tolerance mutant, and we offer a framework for understanding the relationship between initial resistance and tolerance.

neuroscience↗

bioRxiv2021

Animal soil food web complexity triggers shifts in microbial communities, including PAH degraders, but without clear effects on phenanthrene phytoremediation

The aim of this study was to determine whether the complexity of the animal soil food web (SFWC) is a significant factor influencing the soil microbial communities, the productivity of the willow, and the degradation rates of 100 mg kg-1 phenanthrene contamination. The SFWC treatment had eight levels: just the microbial community (BF), or the BF with nematodes (N), springtails (C), earthworms (E), CE, CN, EN, CEN. After eight weeks of growth, the height and biomass of willows were significantly affected by the SFWC, whereas the amount of phenanthrene degraded was not affected, reaching over 95% in all pots. SFWC affected the structure and the composition of the bacterial, archaeal and fungal communities, with significant effects of SFWC on the relative abundance of fungal genera such as Sphaerosporella, a known willow symbiont during phytoremediation, and bacterial phyla such as Actinobacteriota, containing many PAH degraders. These SFWC effects on microbial communities were not clearly reflected in the community structure and abundance of PAH degraders, even though some degraders related to the Actinobacteriota and the diversity of Gram-negative degraders were affected by the SFWC treatments. Overall, our results suggest that, under our experimental conditions, SFWC does not affect significantly willow phytoremediation outcomes. ImportancePolycyclic aromatic hydrocarbons (PAH) pose a threat to soil ecosystems. Phytoremediation is a green technology that can help restore ecosystems health affected by PAH contamination. Past research on phytoremediation of PAH has focused on the roles of plant and microbes in contaminant fates. However, soil environments usually harbor large faunal communities that interact with both the plant and the microbial communities, potentially altering the phytoremediation process. We hypothesized that soil food web complexity (SFWC), represented by increasing levels of soil fauna, influences PAH degradation through interactions with the plant and the microbes. In this study, we demonstrated that SFWC increases the plant biomass and changes the composition of the microbial community, especially the fungal structure. In our pot experiment, more complex levels of SFWC did not contribute to higher degradation rates, but the increased plant biomass and the higher relative abundance of fungal genera associated with lower plant stress could indirectly contribute to better phytoremediation outcomes. Our results highlight the importance of considering the contributions of soil fauna to the success of phytoremediation.

microbiology↗

bioRxiv2021

Endurance Exercise to Improve Physical Function in Adult and Older Mice: High Intensity Interval Training (HIIT) versus Voluntary Wheel Running (VWR)

With age comes a gradual decline in physical function and exercise capacity, concurrent with a progressive propensity for development of sarcopenia /(age-related loss of muscle mass and strength) and frailty (inability of body to thrive and maintain homeostasis). Prior research has demonstrated that exercise, while not a cure, can help mitigate sarcopenia/frailty and restore functional capacity. Reliable, validated, pre-clinical models are necessary to elucidate the underlying molecular mechanisms at the intersection of age, exercise, and functional decline. In this study, we hypothesized that endurance exercise programs mimicking typical human exercise protocols would improve physical function in both adult and older adult mice. Furthermore, our secondary hypothesis was that older mice would receive less benefit from a similar volume of exercise than adult mice. To test these hypotheses, we randomly assigned (with some selection criteria) male C57BL/6 mice either at adult ages during the study (n=24, designated 10m, aged 6 months to 10 months) or at older adult ages (n=18, designated 26m, aged 22 months to 26 months) to a 13-week program of voluntary wheel running (VWR, group termed RUN) or high intensity interval training (HIIT), with an additional 10m sedentary control (CON). The functional aptitude of each mouse was determined pre- and post-training using our composite CFAB (comprehensive functional assessment battery) scoring system consisting of voluntary wheel running (volitional exercise and activity rate), treadmill (endurance), rotarod (overall motor function), grip meter (forelimb strength), and inverted cling (whole body strength/endurance). To measure sarcopenia, we tracked body mass and body composition changes with EchoMRI, and measured muscle wet mass post-training.

physiology↗

bioRxiv2020

Differential alteration of plant functions by homologous fungal candidate effectors

Rust fungi are plant pathogens that cause epidemics that threaten the production of important plant species, such as wheat, soy, coffee and poplar. Melampsora larici-populina (Mlp) causes the poplar rust and encodes at least 1 184 candidate effectors (CEs), however their functions are poorly known. In this study, we used Arabidopsis plants constitutively expressing CEs of Mlp to discover processes targeted by these fungal proteins. For this purpose, we sequenced the transcriptome and used mass spectrometry to analyse the metabolome of Arabidopsis plants expressing individually one of the 14 selected CEs and of a control line. We found 2 299 deregulated genes across the experiment. Among the down-regulated genes, the KEGG pathways "MAPK signaling pathway" and "Plant-pathogen interaction" were respectively over-represented in six and five of the 14 transgenic lines. Moreover, genes related to hormone response and defense were down-regulated across all transgenic lines are. We further observed that there were 680 metabolites deregulated in at least one CE-expressing transgenic line, with highly unsaturated and phenolic compounds enriched in up-regulated metabolites and peptides enriched among down-regulated metabolites. Interestingly, we found that transgenic lines expressing unrelated CEs had correlated patterns of gene and metabolite deregulation, while expression of CEs belonging to the same family deregulated different genes and metabolites. Taken together, our results indicate that the sequence of effectors and their belonging to families may not be a good predictor of their impact on the plant. ImportanceRust fungi are plant pathogens that threaten the production of important crops, including wheat, soy, coffee and poplar. Effectors are used by pathogens to control the host, however in the case of Melampsora larici-populina, the causal agent of the poplar rust, and other rust fungi these proteins are poorly known. We used Arabidopsis plants expressing candidate effectors (CEs) of Mlp to better understand the interaction between this pathogen and its hosts. We found that expression of unrelated CEs led to similar patterns of gene and metabolite deregulation, while transgenic lines expressing CEs belonging to the same family showed different groups of different genes and metabolites deregulated. Thus, our results suggest that functional annotation of effectors based on sequence similarity may be misleading.

plant biology↗

bioRxiv2020

Soil characteristics constrain the response of bacterial and fungal communities and hydrocarbon degradation genes to phenanthrene soil contamination and phytoremediation with poplars

Rhizodegradation is a promising cleanup technology where microorganisms degrade soil contaminants in the rhizosphere. A symbiotic relationship is expected to occur between plant roots and soil microorganisms in contaminated soils that enhance natural microbial degradation in soils. However, little is known about how this initial microbiota influences the rhizodegradation outcome in a context of different soil microbiotas. Recent studies have hinted that soil initial diversity has a determining effect on the outcome of contaminant degradation. To test this hypothesis, we planted (P) or not (NP) balsam poplars (Populus balsamifera) in two soils of contrasting diversity (agricultural and forest) that were contaminated or not with 50 mg kg-1 of phenanthrene (PHE). The DNA from the rhizosphere of the P and the bulk soil of the NP pots was extracted and the bacterial genes encoding for the 16S rRNA, the PAH ring-hydroxylating dioxygenase alpha subunits (PAH-RHD) of gram-positive (GP) and gram-negative (GN) bacteria, and the fungal ITS region were sequenced to characterize the microbial communities. and the abundance of the PAH-RHD genes were also quantified by real-time quantitative PCR. Plant presence had a significant effect on PHE degradation only in the forest soil, whereas both NP and P agricultural soils degraded the same amount of PHE. Bacterial communities were principally affected by the soil type, and upon contamination the dominant PAH degrading community was similarly constrained by soil type. Our results highlight the crucial importance of soil microbial and physicochemical characteristics in the outcome of rhizoremediation.

microbiology↗

bioRxiv2019

Variations in terrestrial arthropod DNA metabarcoding methods recovers robust beta diversity but variable richness and site indicators based on exact sequence variants

Terrestrial arthropod fauna have been suggested as a key indicator of ecological integrity in forest systems. Because phenotypic identification is expert-limited, a shift towards DNA metabarcoding could improve scalability and democratize the use of forest floor arthropods for biomonitoring applications. The objective of this study was to establish the level of field sampling and DNA extraction replication needed for soil arthropod biodiversity assessments. Processing individually collected field samples recovered significantly higher richness (539-596 ESVs) than pooling the same number of field samples (126-154 ESVs), and we found no significant richness differences when using 1 or 3 pooled DNA extractions. Variations in the number of individual or composite samples or DNA extractions resulted in similar sample clustering based on community dissimilarities. Though our ability to identify taxa to species rank was limited, we were able to use arthropod COI metabarcodes from forest soil to assess richness, distinguish among sites, and recover site indicators based on unnamed exact sequence variants. Our results highlight the need to continue DNA barcoding of local taxa during COI metabarcoding studies to help build reference databases. All together, these sampling considerations support the use of soil arthropod COI metabarcoding as a scalable method for biomonitoring.

ecology↗

bioRxiv2019

Altered actin filament dynamics in the Drosophila mushroom bodies lead to fast acquisition of alcohol consumption preference.

Alcohol use is highly prevalent in the United States and across the world, and every year millions of people suffer from alcohol use disorders (AUDs). While the genetic contribution to developing AUDs is estimated to be 50-60%, many of the underlying molecular mechanisms remain unclear. Previous studies from our lab revealed that Drosophila lacking RhoGAP18B and Ras Suppressor 1 (Rsu1) display reduced sensitivity to ethanol-induced sedation. Both Rsu1 and RhoGAP18B are negative regulators of the small Rho-family GTPase, Rac1, a modulator of actin dynamics. Here we investigate the role of Rac1 and its downstream target, the actin-severing protein cofilin, in alcohol consumption preference. We show that these two regulators of actin dynamics can alter experience-dependent alcohol preference in a bidirectional manner: expressing either activated Rac1 or dominant-negative cofilin in the mushroom bodies (MB) abolishes experience-dependent alcohol preference. Conversely, dominant-negative Rac1 or activated cofilin MB expression lead to faster acquisition of alcohol preference. Our data show that Rac1 and cofilin activity are key to determining the rate of acquisition of alcohol preference, revealing a critical role of actin dynamics regulation in the development of voluntary self-administration in Drosophila.\n\nSignificance StatementThe risks for developing an alcohol use disorder (AUD) are strongly determined by genetic factors. Understanding the genes and molecular mechanisms that contribute to that risk is therefore a necessary first step for the development of targeted therapeutic intervention. Here we show that regulators of actin cytoskeleton dynamics can bidirectionally determine the acquisition rate of alcohol self-administration, highlighting this process as a key mechanism contributing to the risk of AUD development.

neuroscience↗