Biology subjects

Grandgirard, E.

Publications and source records attributed to Grandgirard, E..

8 recordsLinked to original sources

bioRxiv2026

Satellite cell glucocorticoid receptor restrains myogenic commitment without mediating the effects of therapeutic glucocorticoids on muscle repair

Glucocorticoids (GCs) exert profound effects on skeletal muscle, but the contribution of satellite cell (SatC) glucocorticoid receptor (GR) signaling to muscle regeneration remains poorly understood. Here, we investigated the role of GR in SatC homeostasis and assessed whether SatC GR mediates the effects of therapeutic GCs on muscle repair. Conditional deletion of GR in SatC reduced the number of PAX7-positive cells during regeneration in young mice, but did not substantially impair muscle repair in either young or aged animals. Transcriptomic and chromatin profiling revealed that GR occupies genes involved in stem cell fate and developmental signaling, with extensive GR binding already established in quiescent SatC. GR-deficient quiescent SatC showed reduced expression of Yap1, Runx1 and Foxo1, together with increased Myog expression. Similarly, GR silencing in human myoblasts induced early myogenic differentiation markers without affecting proliferation, supporting a conserved role for GR in restraining myogenic commitment. We next examined the effects of two therapeutic GCs on muscle regeneration. Chronic prednisone treatment altered the transcriptional landscape of regenerating muscle in an age-dependent manner, without substantially affecting histological repair. In contrast, dexamethasone administration during the early inflammatory phase delayed regeneration, with persistent necrosis and increased collagen deposition. These effects were comparable in control and SatC-specific GR-deficient mice, indicating that they do not require GR in SatC. Together, these findings identify GR as a regulator of the quiescent, undifferentiated state of SatC, while showing that the effects of therapeutic GCs on muscle repair are largely independent of SatC GR. They further highlight the importance of treatment regimen and physiological context in determining the effects of GCs on skeletal muscle regeneration.

physiology↗

bioRxiv2026

Asymmetric distribution of actin-related proteins in the early C. elegans embryo.

Embryos experience challenges when transforming a passive oocyte into a polarized embryo. In Caenorhabditis elegans, polarisation is initiated at the one-cell stage and followed by a series of asymmetric or symmetric cell divisions. Patterns emerge via the regulated segregation of molecules at each cell division, including polarity proteins, cell fate determinants, transcription factors, mRNAs, and actin. The actomyosin cytoskeleton plays a crucial role in these early differentiation events, but how actin itself is segregated asymmetrically during the first divisions of the zygote remains poorly understood. This study presents a thorough quantification of the spatiotemporal distribution of actin, the actin nucleators CYK-1 and Arp2/3 Complex, the capping protein CAP-1, and the E-cadherin HMR-1, from the zygote up to the 4-cell stage. To determine the potential for actin assembly of each early embryonic cell, we developed a novel assay combining in vivo microscopy-based quantitative analysis of the cytoskeleton, with in vitro actin polymerisation assays from single cell extracts named SCOPE-Single Cell cytOPlasm Extraction. SCOPE relies on UV laser ablation to empty blastomere cells into a polymerisation competent environment while following subsequent actin polymerisation. We find asymmetric segregations of most cytoskeleton proteins in favour of larger cells in a manner that is dependent on PAR polarity cues. AB and EMS cells being notably actively enriched compared to their sister cells, P cells being maintained in a state of low actin filaments. Interestingly, we discover an enrichment in ABp compared to ABa as division occurs, demonstrating that symmetric cell divisions are not exempt of actin enrichment. Additionally, this result illustrates that asymmetric distribution of actin-related proteins can precede known cell differentiation events. Taken together, these cytoskeleton heterogeneities are adding a layer to the complexity of cell fate acquisition mechanisms in the early embryo. Significance StatementO_LIThe embryonic cytoskeleton can be actively inherited rather than passively distributed during early development. C_LIO_LIActin assembly capacity can differ between blastomeres before fate diversification. C_LIO_LIDifferential inheritance of actin regulatory machinery represents a potential mechanism linking cell polarity to developmental cell fate decisions. C_LI

developmental biology↗

bioRxiv2025

Androgen receptor imprints satellite cells stemness and preserves their reservoir for lifelong regeneration and optimal repair

Skeletal muscle stem cells (MuSC) are the guardians of muscle regeneration, sustaining tissue integrity through a delicate balance of quiescence, activation, and lineage commitment. While numerous molecular cues have been implicated in regulating these processes, the influence of androgen receptor (AR) signaling, an essential hormonal pathway for male muscle physiology, has remained largely unexplored. Here, we show that AR expression defines quiescent MuSC and acts as a safeguard of their dormancy. Integrated multi-omic analyses reveal a redistribution of AR binding from quiescence-maintenance loci to regulatory elements driving activation and metabolic reprogramming during repair. Loss of AR in young adult mice disrupts this balance, precipitating premature cell-cycle entry, skewed division modalities, depletion of the stem cell reservoir, and destabilization of the niche. These defects converge with hallmarks of aging-associated androgen decline, while androgen supplementation restores regenerative competence. Together, our findings establish AR signaling as a pivotal determinant of MuSC fate and a cornerstone of skeletal muscle homeostasis.

developmental biology↗

bioRxiv2025

Glucocorticoid Receptor Signaling in Myeloid Cells Orchestrates Inflammation Resolution and Muscle Repair

Glucocorticoids are key regulators of inflammation and tissue repair, yet their precise role in muscle regeneration remains incompletely understood. Here, we investigate the impact of myeloid-specific glucocorticoid receptor (GR) invalidation on macrophage dynamics and muscle stem cell function following acute injury. We demonstrate that the loss of GR in myeloid cells leads to increased macrophage accumulation, driven by altered proliferation and recruitment, without affecting fibro-adipogenic progenitor differentiation or satellite cell proliferation and differentiation under steady-state conditions. Transcriptomic and cistrome analyses at early regeneration stages reveal that GR directly regulates gene networks involved in efferocytosis and cell cycle control in myeloid cells. Importantly, administration of dexamethasone during the pro-inflammatory phase markedly delays muscle regeneration by impairing monocyte-to-macrophage transition and promoting macrophage proliferation in a myeloid-GR dependent manner, ultimately reducing satellite cell proliferation and myogenesis. In contrast, dexamethasone treatment during the anti-inflammatory phase exerts limited effects on muscle recovery. Together, our findings uncover a critical temporal role of GR signaling in myeloid cells in coordinating inflammatory resolution and stem cell function during muscle repair, and highlight the complexity of glucocorticoid actions in regenerative contexts.

developmental biology↗

bioRxiv2025

NUCGEN3D: A synthetic framework for large-scale 3D nuclear segmentation with open-source training data and models

AO_SCPLOWBSTRACTC_SCPLOWRobust nuclear segmentation in 3D microscopy images is a critical yet unresolved challenge in quantitative cell biology, hindered by the scarcity and variability of annotated volumetric datasets. Because such data are difficult to obtain, most state-of-the-art approaches, including Cellpose, segment individual 2D slices and then heuristically reconstruct 3D volumes, thereby losing critical spatial context. Our analysis of expert annotator performance confirms that ignoring 3D context introduces substantial variability in nuclear detection and annotation. While a few 3D models have been trained on small or toy datasets, no large-scale, openly available resource currently exists to enable robust training of high-capacity 3D segmentation networks. To address this, we present NucGen3D, a customizable simulation framework that generates large-scale, annotated 3D microscopy datasets from limited 2D input, specifically the 2018 Data Science Bowl dataset. NucGen3D produces realistic 3D volumes across diverse biological and imaging scenarios, including variations in nuclear morphology, spatial arrangement, acquisition artifacts, and imaging noise. Using this synthetic data, we trained two models from scratch: a 2D convolutional neural network under Cellpose-like conditions, and a fully 3D convolutional model that extends the 2D settings. We evaluated both on a challenging, independent real-world dataset with complex nuclear architectures. Both models, especially the 3D model, consistently outperformed state-of-the-art methods, including those trained on larger annotated datasets or based on more complex architectures. These results demonstrate that synthetic data can effectively substitute for real 3D annotations in training performing models at scale. To promote reproducibility and further research, we release both the NucGen3D framework and the fully trained 3D segmentation model as open source, making this the first end-to-end open resource for large-scale 3D nuclear segmentation.

bioinformatics↗

bioRxiv2023

Competition between transcription and loop extrusion modulates promoter and enhancer dynamics

The spatiotemporal configuration of genes with distal regulatory elements, and the impact of chromatin mobility on transcription, remain unclear. Loop extrusion is an attractive model for bringing genetic elements together, but how this functionally interacts with transcription is also largely unknown. We combine live tracking of genomic loci and nascent transcripts with molecular dynamics simulations to assess the 4D arrangement of the Sox2 gene and its enhancer, in response to a battery of perturbations. We find that alterations in chromatin mobility, not promoter-enhancer distance, is more informative about transcriptional status. Active elements display more constrained mobility, consistent with confinement within specialized nuclear sites, and alterations in enhancer mobility distinguish poised from transcribing alleles. Strikingly, we find that whereas loop extrusion and transcription factor-mediated clustering contribute to promoter-enhancer proximity, they have antagonistic effects on chromatin dynamics. This provides an experimental framework for the underappreciated role of chromatin dynamics in genome regulation.

cell biology↗

bioRxiv2022

UBAP2L-dependent coupling of PLK1 localization and stability during mitosis

PLK1 is an important regulator of mitosis whose protein levels and activity fluctuate during the cell cycle. PLK1 dynamically localizes to various mitotic structures to regulate chromosome segregation. However, the signaling pathways linking localized PLK1 activity to its protein stability remain elusive. Here, we identify the Ubiquitin-Binding Protein 2-Like (UBAP2L) that controls both, the localization and the protein stability of PLK1.We demonstrate that UBAP2L is a spindle-associated protein whose depletion leads to severe mitotic defects. UBAP2L depleted cells are characterized by increased PLK1 protein levels and abnormal PLK1 accumulation in several mitotic structures such as kinetochores, centrosomes and mitotic spindle. UBAP2L deficient cells exit mitosis and enter the next interphase in the presence of aberrant PLK1 kinase activity. The C-terminal domain of UBAP2L mediates its function on PLK1 independently of its role in stress response signaling. Importantly, the mitotic defects of UBAP2L depleted cells are largely rescued upon chemical inhibition of PLK1. Overall, our data suggest that UBAP2L is required to finetune the ubiquitin-mediated PLK1 turnover during mitosis as a means to maintain genome fidelity.

cell biology↗

bioRxiv2021

CaMK1D signaling in AgRP neurons promotes ghrelin-mediated food intake

Hypothalamic AgRP/NPY neurons are key players in the control of feeding behavior. Ghrelin, a major hormone released under fasting conditions, activates orexigenic AgRP/NPY neurons to stimulate food intake and adiposity. However, cell-autonomous ghrelin-dependent signaling mechanisms in AgRP/NPY neurons remain poorly defined. Here we demonstrate that calcium/calmodulin-dependent protein kinase ID (CaMK1D), a genetic hot spot in type 2 diabetes, is activated in hypothalamus upon ghrelin stimulation and acts in AgRP neurons to promote ghrelin-dependent food intake. Global CaMK1D knockout mice are resistant to the orexigenic action of ghrelin, gain less body weight and are protected against high-fat diet-induced obesity. Deletion of CaMK1D in AgRP but not in POMC neurons is sufficient to recapitulate above phenotypes. Lack of CaMK1D attenuates phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP/NPY as well as the amount of AgRP fiber projections to the Paraventricular nucleus (PVN), while electrical activity of AgRP neurons and 5 AMP-activated protein kinase (AMPK) signaling are unaffected. Hence, CaMK1D links ghrelin action to transcriptional control of orexigenic neuropeptide availability in AgRP neurons. HighlightsO_LIWhole-body deletion of CaMK1D in mice reduces food intake, ghrelin sensitivity and protects against obesity. C_LIO_LIAgRP/NPY neuron-specific deletion of CaMK1D reduces food intake, ghrelin sensitivity, energy expenditure and protects against obesity. C_LIO_LICaMK1D is dispensable for ghrelin-stimulated electrical activity of AgRP neurons and hypothalamic AMPK signaling. C_LIO_LICaMK1D controls phosphorylation of CREB and CREB-dependent expression of the orexigenic neuropeptides AgRP and NPY. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/471546v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@40d7d7org.highwire.dtl.DTLVardef@11a8c64org.highwire.dtl.DTLVardef@1f6fad3org.highwire.dtl.DTLVardef@1cd5581_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗