2025
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- The insertion of Neomycin cassette impairs maternal and social behaviors in Arc/Arg3.1 knock-out mice
- article
- 2025
- resume
- The Neomycin resistance cassette (Neo+) is commonly inserted in the genome of mice to generate knock-out (KO) models. The effect of gene deletion on social behaviors in mice is controversial between studies using different Neo+ and Neo- mouse lines, particularly Arc/Arg3.1 KO lines. In this study, we identified severe maternal behavior impairments in Neo+, but not Neo- Arc/Arg3.1 KO dams. These deficits resulted from reduced sociability and abnormal social information processing in Neo+ Arc/Arg3.1 KO dams, exacerbated by social communication impairments in pups. The expression of the Neo cassette product did not cause cytotoxicity, but led to altered ERK signaling, gene expression, and oxytocin system. However, oxytocin administration did not improve social impairments in Neo+ Arc/Arg3.1 KO animals. Interestingly, early social environment enrichment enhanced social interaction with familiar, but not unfamiliar conspecifics or maternal behavior. Overall, our findings reveal a major impact of the Neo cassette on behaviors, particularly social behaviors, in Arc/Arg3.1 KO mice, underscoring the need to re-examine phenotypes of animal models carrying the Neo cassette in neuroscience research.
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- titre
- Rapid cell turnover to model adipocyte size distribution
- article
- 2025
- resume
- White adipose tissue, composed of adipocyte cells, primarily stores energy as lipid droplets. The size of adipocytes varies significantly within the tissue due to the amount of stored lipids, and their size distribution is uniquely bimodal, lacking a characteristic size. Previous modeling efforts to understand these characteristics fall into two categories. On the one hand, models that aim at replicating bimodality using general parameters: their broad nature makes it hard to associate with physiological mechanisms. On the other hand, mechanistic models are usually based on lipid exchanges and neglect cell renewal assuming adipocyte turnover is low. We propose a novel dynamical model, based on a partial differential equation, where adipocytes are constantly growing in size, and when growth is slowed for a certain size, cells tend to accumulate at this size. In addition, it includes a recruitment and a death rate accounting for turnover. This model admits a unique stationary solution, locally asymptotically stable, for a wide choice of problem functions. The stationary solution is parameterized with 3 parameters, that are uniquely estimated with measured cell size distributions. This explicit function gives a new way to fit adipocyte size distributions with only three parameters, which is a novel approach and gives results in good agreement with available data.
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- titre
- Hormone-regulated dynamics of mRNA distribution on ribosomes in Sertoli cells
- article
- 2025
- resume
- The effects of hormone stimulation on the cell translational profile remain poorly understood. Here, using polysome profiling combined to RNA sequencing, we analyzed the translational response to follicle-stimulating hormone (FSH) of primary rat Sertoli cells, that exhibit an active anabolic activity regulated by reproductive hormones in the male gonad. We first established that mRNA distribution to polysomes follows a bimodal pattern, with 15% of mRNAs enriched in polysomes and exhibiting high expression. Critically, this basal polysomal enrichment had a major impact on FSH-induced mRNA recruitment to the polysomes, since FSH stimulation promoted the release of polysome-enriched mRNAs, while mRNAs that were the least associated to polysomes were preferentially recruited to polysomes upon stimulation. The FSH signal did not alter the core biological functions of Sertoli cells, but shifted the proteins involved in these functions, suggesting a molecular rewiring of the FSH-induced gene expression. These findings underscore how ribosomal reallocation dynamically adapts the cellular translatome to microenvironmental changes, enabling cells to fine-tune protein production in response to external stimuli. GRAPHICAL ABSTRACT Bullet points • In Sertoli cells, most mRNAs distribute similarly between monosomes and polysomes, but a sub-population is specifically enriched in polysomes • Basal polysomal enrichment level has a major impact on FSH-induced mRNA recruitment or release from the polysomes • The FSH signal induced a global rewiring of the proteins involved in Sertoli cell basal activity • FSH-induced reassignment of ribosomes to specific mRNAs has to comply with a tightly maintained mRNA distribution landscape
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2024
- titre
- Well-posedness and bifurcation analysis of a size-structured population model: Application to female gametes dynamics
- article
- 2024
- resume
- We introduce and analyze a quasilinear size-structured population model with nonlinearities accounting for nonlocal interactions between individuals. The recruitment (immigration), growth and death rates are inhomogeneous in time and/or space and depend on weighted averages of the density. We first prove the existence and uniqueness of globally bounded weak solutions using the characteristic curves and Banach fixed point Theorem, after transforming the partial differential equation into an equivalent system of integral equations. We then investigate the long-time behavior of the PDE in the case when the growth rate is separable. Applying a classical time-scaling transformation, the problem boils down to a PDE with linear growth rate and nonlinear inflow boundary condition, entering the theoretical framework of abstract semilinear Cauchy problems. We can then perform a bifurcation analysis which reveals the richness of the model behavior. Depending on the ratio of the recruitment to the growth rate, the model can exhibit multistability and stable oscillatory solutions, emanating respectively through saddle-node and Hopf bifurcations. We illustrate these theoretical results on the biological application motivating this work, oogenesis, the process of production and maturation of female gametes (oocytes) that is critical to reproductive fitness.
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- Targeting selectively oxytocin receptor signalling efficiently improves social interaction in Fmr1 KO mice
- article
- 2024
- resume
- Background and Purpose: No drugs targeting the core social features of autism spectrum disorder (ASD) have been approved. Although clinical trials with oxytocin (OT) and vasopressin (AVP) have yielded mixed results, targeting their receptors remains the most promising pharmacological strategy for addressing social impairments in ASD. This study aims to identify which receptors and signalling pathways within this family can sustainably improve social impairments. Experimental Approach: We used dose-response and kinetic analyses, along with mathematical modelling, to evaluate OT, AVP, their homologs, and novel synthetic ligands on G protein coupling, β-arrestins recruitment, and internalisation of mouse oxytocin (OTR) and vasopressin (V1A, V1B, V2) receptors in Neuro-2a cells. We tested acute and subchronic administration of OTR agonists and the novel V1A receptor antagonist, alongside OT and AVP, for their effects on social interaction in Fmr1 KO mice, a model exhibiting ASD-like features. Key Results: While OT, AVP and most compounds were non-selective across the four receptors, the OTR agonists TGOT or RO6958375 and the V1A antagonist RO6893074 were selective. TGOT or RO6958375, favouring Gαq signalling, enhanced social interactions in Fmr1 KO mice while showing minimal effects in wild-type mice. In contrast, OT, AVP or RO6893074 exhibited limited efficacy in Fmr1 KO mice. Conclusion and Implications: Selective OTR agonists, unlike OT and AVP, effectively improved social impairments in Fmr1 KO mice after acute and subchronic treatment. These findings highlight the necessity for developing highly selective OTR Gαq-biased agonists to achieve clinical outcomes in ASD.
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