Biology subjects

Perez, Y.

Publications and source records attributed to Perez, Y..

11 recordsLinked to original sources

bioRxiv2025

Cortical tension as a mechanical barrier to safeguard against premature differentiation during neurogenesis

Neuronal differentiation requires coordinated gene reprogramming and morphodynamic remodeling. How mechanical forces integrate with nuclear gene programs during neurogenesis remains unresolved. Here, we identify cortical tension as a mechanical barrier that safeguards against premature neuronal differentiation. Deletion of Plexin-B2, a guidance receptor controlling actomyosin contractility, lowers this barrier, enabling neurite outgrowth and accelerating neuronal lineage commitment. We show that coupling of extrinsic differentiation cues with intrinsic morphodynamics is essential for stabilizing neuronal fate and that cortical barrier and epigenetic barrier act in concert to regulate developmental timing. In cerebral organoids, Plexin-B2 ablation triggered premature cell-cycle exit and differentiation, resulting in progenitor pool depletion and neuroepithelial disorganization, phenotypes echoing intellectual disability in patients with rare pathogenic PLXNB2 variants. Our studies demonstrate that cortical tension functions as mechano-checkpoint that regulates the onset of neurogenesis. Lowering this barrier may provide a strategy to accelerate induced neuron generation and maturation for CNS disease modeling.

neuroscience↗

bioRxiv2024

Adhesion G protein-coupled receptor ADGRG1 promotes protective microglial response in Alzheimer's disease

Germline genetic architecture of Alzheimers disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms that enable microglia to mediate protective responses to AD pathology remain elusive. Adgrg1 is specifically expressed in yolk-sac-derived microglia. This study reveals the role of yolk-sac-derived microglia in AD pathology, highlighting the function of ADGRG1 in modulating microglial protective responses to amyloid deposition. Utilizing both constitutive and inducible microglial Adgrg1 knockout 5xFAD models, we demonstrate that Adgrg1 deficiency leads to increased amyloid deposition, exacerbated neuropathology, and accelerated cognitive impairment. Transcriptomic analyses reveal a distinct microglial state characterized by downregulated genes associated with homeostasis, phagocytosis, and lysosomal functions. Functional assays in mouse models and human embryonic stem cells-derived microglia support that microglial ADGRG1 is required for efficient A{beta} phagocytosis. Together, these results uncover a GPCR-dependent microglial response to A{beta}, pointing towards potential therapeutic strategies to alleviate disease progression by enhancing microglial functional competence.

neuroscience↗

bioRxiv2024

Fate plasticity of interneuron specification

The generation of neuronal subtypes in the mammalian central nervous system is driven by competing genetic programs. The medial ganglionic eminence (MGE) gives rise to two major cortical interneuron (cIN) populations, marked by Somatostatin (Sst) and Parvalbumin (Pvalb), which develop on different timelines. The extent to which external signals influence these identities remains poorly understood. Pvalb-positive cINs are particularly important for regulating cortical circuits through strong perisomatic inhibition, yet they have been difficult to model in vitro. Here we investigated the role of the environment in shaping and maintaining Pvalb cINs. We grafted mouse MGE progenitors into a variety of 2D and 3D co-culture models, including mouse and human cortical, MGE, and thalamic systems with dissociated cells, organoids, organotypic cultures, and conditioned media. Across models, we observed distinct proportions of Sst- and Pvalb-positive cIN descendants. Strikingly, grafting MGE progenitors into 3D human, but not mouse, corticogenesis models led to efficient, non-autonomous differentiation of Pvalb-positive cINs. This differentiation was characterized by upregulation of Pvalb maturation markers, downregulation of Sst-specific markers, and the formation of perineuronal nets. Furthermore, lineage-traced postmitotic Sst-positive cINs, when grafted onto human cortical models, also upregulated Pvalb expression. These results reveal an unexpected level of fate plasticity in MGE-derived cINs, demonstrating that their identities can be dynamically shaped by the surrounding environment.

neuroscience↗

bioRxiv2024

Sex-Specific Changes in Cardiac Function and Electrophysiology During Progression of Adenine-Induced Chronic Kidney Disease in Mice

BACKGROUNDChronic kidney disease (CKD) and cardiovascular disease (CVD) often co-exist and interact; however, notable sex-dependent differences are observed in how these conditions manifest and progress in parallel, despite men and women sharing similar risk factors. Identifying sex-specific diagnostic markers of cardiac structure and function throughout CKD progression could elucidate why the development and progression of these diseases differ by sex. METHODS AND RESULTSAdult, C57BL/6J male and female mice were subjected to a high-adenine (0.2%) diet throughout 12-weeks to induce CKD. Control mice were fed a normal chow diet. Every three weeks, electrocardiogram (ECG) and echocardiogram-based markers of cardiac physiology were evaluated. Adenine-induced CKD showed markers of left ventricular (LV) hypertrophy in male mice only. CKD males had markers indicative of LV systolic and diastolic dysfunction throughout regimen duration, worsening as disease progressed. Adenine males had a prolonged QTc and STc intervals when compared to Adenine females and Control males. Sex-dependent differences in the duration of the Speak-J marker, measured via ECG, was identified, with Adenine males showing increases in duration earlier than Adenine females compared to their Control counterparts. CONCLUSIONSIn this study, we identified sex-dependent differences in cardiac structure, function, and electrophysiology in a mouse model of CKD-induced CVD throughout disease progression. We found that male mice are more prone to developing LV hypertrophy, systolic dysfunction, and diastolic dysfunction, with significant increases in ECG markers indicative of ventricular dysfunction observed in adenine-treated males at late stages of the disease. Additionally, we identified a new ECG parameter, Speak-J duration, that highlights sex-specific cardiac electrophysiological changes, demonstrating the models utility in studying sex-dependent cardiac differences.

pathology↗

bioRxiv2023

Single cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism

Duplication 15q (dup15q) syndrome is the most common genetic cause of autism spectrum disorder (ASD). Due to a higher genetic and phenotypic homogeneity compared to idiopathic autism, dup15q syndrome provides a well-defined setting to investigate ASD mechanisms. Previous bulk gene expression studies identified shared molecular changes in ASD. However, how cell type specific changes compare across different autism subtypes and how they change during development is largely unknown. In this study, we used single cell and single nucleus mRNA sequencing of dup15q cortical organoids from patient iPSCs, as well as post-mortem patient brain samples. We find cell-type specific dysregulated programs that underlie dup15q pathogenesis, which we validate by spatial resolved transcriptomics using brain tissue samples. We find degraded identity and vulnerability of deep-layer neurons in fetal stage organoids and highlight increased molecular burden of postmortem upper-layer neurons implicated in synaptic signaling, a finding shared between idiopathic ASD and dup15q syndrome. Gene co-expression network analysis of organoid and postmortem excitatory neurons uncovers modules enriched with autism risk genes. Organoid developmental modules were involved in transcription regulation via chromatin remodeling, while postmortem modules were associated with synaptic transmission and plasticity. The findings reveal a shifting landscape of ASD cellular vulnerability during brain development.

neuroscience↗

bioRxiv2023

Surveillance of Vermont wildlife in 2021-2022 reveals no detected SARS-CoV-2 viral RNA

Previous studies have documented natural infections of SARS-CoV-2 in various domestic and wild animals. More recently, studies have been published noting the susceptibility of members of the Cervidae family, and infections in both wild and captive cervid populations. In this study, we investigated the presence of SARS-CoV-2 in mammalian wildlife within the state of Vermont. 739 nasal or throat samples were collected from wildlife throughout the state during the 2021 and 2022 harvest season. Data was collected from red and gray foxes (Vulpes vulples and Urocyon cineroargentus, respectively), fishers (Martes pennati), river otters (Lutra canadensis), coyotes (Canis lantrans), bobcats (Lynx rufus rufus), black bears (Ursus americanus), and white-tailed deer (Odocoileus virginianus). Samples were tested for the presence of SARS-CoV-2 via quantitative RT-qPCR using the CDC N1/N2 primer set and/or the WHO-E gene primer set. Our results indicate that no sampled wildlife were positive for SARS-CoV-2. This finding is surprising, given that most published North America studies have found SARS-CoV-2 within their deer populations. The absence of SARS-CoV-2 RNA in populations sampled here may provide insights in to the various environmental and anthropogenic factors that reduce spillover and spread in North Americans wildlife populations.

microbiology↗

bioRxiv2022

A cross-species proteomic map of synapse development reveals neoteny during human postsynaptic density maturation

The molecular mechanisms and evolutionary changes accompanying synapse development are still poorly understood. Here, we generated a cross-species proteomic map of synapse development in the human, macaque, and mouse neocortex. By tracking the changes of >1,000 postsynaptic density (PSD) proteins from midgestation to young adulthood, we found that PSD maturation in humans separates into three major phases that are dominated by distinct pathways. Cross-species comparisons reveal that the human PSD matures about two to three times slower than other species and contains higher levels of Rho guanine nucleotide exchange factors (RhoGEFs) in the perinatal period. Enhancement of the RhoGEF signaling in human neurons delays the morphological maturation of dendritic spines and the functional maturation of synapses, potentially contributing to the neotenic traits of human brain development. In addition, PSD proteins can be divided into four modules that exert stage- and cell type-specific functions, possibly explaining their differential associations with cognitive functions and diseases. Together, our proteomic map of synapse development provides a blueprint for studying the molecular basis and evolutionary changes of synapse maturation.

neuroscience↗

bioRxiv2022

Single-cell analysis of prenatal and postnatal human cortical development

We analyze more than 700,000 single-nucleus RNA-seq profiles from 106 donors during prenatal and postnatal developmental stages and identify lineage-specific programs that underlie the development of specific subtypes of excitatory cortical neurons, interneurons, glial cell types and brain vasculature. By leveraging single-nucleus chromatin accessibility data, we delineate enhancer-gene regulatory networks and transcription factors that control commitment of specific cortical lineages. By intersecting our results with genetic risk factors for human brain diseases, we identify the cortical cell types and lineages most vulnerable to genetic insults of different brain disorders, especially autism. We find that lineage-specific gene expression programs upregulated in female cells are especially enriched for the genetic risk factors of autism. Our study captures the molecular progression of cortical lineages across human development. One Sentence SummarySingle-cell transcriptomic atlas of human cortical development identifies lineage and sex-specific programs and their implication in brain disorders.

neuroscience↗

bioRxiv2021

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms, which range in severity, accompany a significant proportion of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 and CD147. Inhibition of DPP4 reduced infection and decreased expression of the cell stress marker, ARCN1. We find tropism of SARS-CoV-2 for human astrocytes mediated by DPP4, resulting in reactive gliosis-type injury.

neuroscience↗

bioRxiv2018

Characterisation of palytoxin from an undescribed Palythoa (Anthozoa: Zoantharia: Sphenopidae) with significant in vitro cytotoxic effects on cancer cells at picomolar doses

Palytoxin (PlTX), a large polyhydroxylated compound, is among the most potent non-peptide toxin in marine organisms known so far. The literature emphasizes the sodium/potassium pump (NaK) as the privileged target for PlTX when exerting its toxic effects. In this study, we focused on an undescribed species (Palythoa sp. Pc001), a coral species belonging to the genus Palythoa routinely cultivated in aquariums. We demonstrated that this species contains one of the highest yields of pure PlTX production ever found, 2.22 {+/-} 0.41 mg PlTX per gram of wet Palythoa. Using molecular data combined with external morphology, we identified Palythoa sp. Pc001 as the sister species to Palythoa aff. clavata. Further, the clade of a symbiotic Symbiodinium sp. was characterised by DNA barcoding and pigment content. Molecular data showed that Palythoa sp. Pc001 contains generalist Symbiodinium belonging to clade C. This paper also describes for the first time the localisation of PlTX and Symbiodinium cells in tissues of a highly toxic Palythoa species. PlTX toxicity was assayed on 72 h-cultured murine and human cancer cells versus the normal human dermal fibroblast (NHDF; PC C12300) cell line. Using MTT colorimetric assay and quantitative videomicroscopy, our results showed much higher in vitro cytotoxic activity on cancer cells (IC50 0.54 {+/-} 0.05 x 10-12 M) than on non-cancerous ones (IC50 > 1 x 10-6 M). Such a strong differential effect has never been reported with respect to the most potent NaK ligands (cardiac glycosides) described so far. Moreover, PlTX displayed similar in vitro growth inhibitory activity in rodent and human cancer cells, although the NaK in rodents displays a double mutation in the 1-subunit that usually decreases the sensitivity to others cardiac glycosides like ouabain, when compared to human cells. This work demonstrates, first, that picomolar concentrations of PlTX have significant higher cytotoxic effects on cancer cells than on non-cancerous ones, and secondly, that this in vitro antitumor effect would not be entirely relied onto its canonical targeting to the NaK -subunit. Thus, PlTX ranks amongst highly potent anti-cancer drugs as it targets cancers while potentially minimizing the drugs side effects on healthy cells.

cancer biology↗

bioRxiv2017

A Complete Logical Approach to Resolve the Evolution and Dynamics of Mitochondrial Genome in Bilaterians

A new method of genomic maps analysis based on formal logic is described. The purpose of the method is to 1) use mitochondrial genomic organisation of current taxa as datasets 2) calculate mutational steps between all mitochondrial gene arrangements and 3) reconstruct phylogenetic relationships according to these calculated mutational steps within a dendrogram under the assumption of maximum parsimony. Unlike existing methods mainly based on the probabilistic approach, the main strength of this new approach is that it calculates all the exact tree solutions with completeness and provides logical consequences as very robust results. Moreover, the method infers all possible hypothetical ancestors and reconstructs character states for all internal nodes (ancestors) of the trees. We started by testing the method using the deuterostomes as a study case. Then, with sponges as an outgroup, we investigated the mutational network of mitochondrial genomes of 47 bilaterian phyla and emphasised the peculiar case of chaetognaths. This pilot work showed that the use of formal logic in a hypothetico-deductive background such as phylogeny (where experimental testing of hypotheses is impossible) is very promising to explore mitochondrial gene rearrangements in deuterostomes and should be applied to many other bilaterian clades.\n\nAuthor SummaryInvestigating how recombination might modify gene arrangements during the evolution of metazoans has become a routine part of mitochondrial genome analysis. In this paper, we present a new approach based on formal logic that provides optimal solutions in the genome rearrangement field. In particular, we improve the sorting by including all rearrangement events, e.g., transposition, inversion and reverse transposition. The problem we face with is to find the most parsimonious tree(s) explaining all the rearrangement events from a common ancestor to all the descendants of a given clade (hereinafter PHYLO problem). So far, a complete approach to find all the correct solutions of PHYLO is not available. Formal logic provides an elegant way to represent and solve such an NP-hard problem. It has the benefit of correctness, completeness and allows the understanding of the logical consequences (results true for all solutions found). First, one must define PHYLO (axiomatisation) with a set of logic formulas or constraints. Second, a model generator calculates all the models, each model being a solution of PHYLO. Several complete model generators are available but a recurring difficulty is the computation time when the data set increases. When the search of a solution takes exponential time, two computing strategies are conceivable: an incomplete but fast algorithm that does not provide the optimal solution (for example, use local improvements from an initial random solution) or a complete - and thus not efficient - algorithm on a smaller tractable dataset. While the large amount of genes found in the nuclear genome strongly limits our possibility to use of formal logic with any conventional computer, we show in our paper that, for bilaterian mtDNAs, all the correct solutions can be found in a reasonable time due to the small number of genes.

bioinformatics↗