Biology subjects

Ango, F.

Publications and source records attributed to Ango, F..

6 recordsLinked to original sources

bioRxiv2026

Raf-MEK-ERK signaling mediates FLT3-induced mechanical allodynia and reduced morphine analgesic efficacy in male rodents

The cytokine FL and its receptor, Fms-like tyrosine kinase 3 (FLT3), contribute to chronic pain and to the maladaptive effects of morphine but the intracellular mechanisms underlying these effects remain incompletely understood. Here, we investigated the contribution of the Raf-MEK-ERK pathway to FLT3dependent nociceptive signaling and to the modulation of morphine analgesia. Using HEK293T cells expressing human or mouse FLT3, primary dorsal root ganglion (DRG) neurons, and rodent models, we examined ERK activation, TRPV1 sensitization, and behavioral responses following FLT3 activation by its ligand, FL. FL induced concentration-dependent ERK phosphorylation through FLT3, while pharmacological inhibition of FLT3, Raf, or MEK reduced this response. In primary DRG neurons, MEK inhibition attenuated FLinduced potentiation of capsaicin-evoked calcium responses, supporting a role for MEK-ERK signaling in TRPV1 sensitization. In vivo, intrathecal FL increased ERK phosphorylation in DRGs and induced mechanical hypersensitivity, both of which were reduced by Raf or MEK inhibition. In FLT3/MOR-expressing cells, morphine potentiated FL-induced ERK activation, an effect reduced by naloxone and abolished by FLT3 inhibition. In rats, MEK inhibition prevented the FL-induced reduction of morphine analgesia and subsequent mechanical hypersensitivity. Together, these findings identify Raf-MEK-ERK signaling as an important downstream pathway linking neuronal FLT3 activation to nociceptor sensitization and impaired morphine analgesic efficacy.

neuroscience↗

bioRxiv2025

FL/FLT3 signaling enhances mechanical pain hypersensitivity through Interleukin-1 beta (IL-1β) in male mice

Fms-like tyrosine kinase 3 (FLT3) plays a critical role in chronic pain through its ligand FL, a cytokine that triggers mechanical pain hypersensitivity. However, the underlying molecular mechanisms remain unclear. Here, we investigate the potential interplay between FL and IL-1{beta} a key cytokine in DRG neurons sensitization and mechanical hyperalgesia through both in vitro and in vivo approaches. ELISA assays reveal that intrathecal FL administration significantly increases IL-1{beta} protein levels in both the DRG and dorsal spinal cord of mice, beginning four hours post-injection. Using video microscopy and [Ca2+]i fluorescence imaging in primary DRG neuron cultures, we demonstrate that FL potentiation of TRPV1 receptor responses to capsaicin is partially mediated by IL-1{beta} signalling, as evidenced by a significant reduction in this potentiation in the presence of the IL-1 receptor antagonist, IL-1Ra. Furthermore, FLT3-driven acute mechanical pain hypersensitivity in vivo is reduced both by prior administration of IL-1Ra and in IL-1 receptor knockout mice. Importantly, IL-1{beta}-induced mechanical pain hypersensitivity remains independent of FLT3 signalling as shown in Flt3 knockout mice. Collectively our findings expand the understanding of neuro-immune interactions by demonstrating a potential functional link between FL/FLT3 and IL-1{beta}/IL-1R signalling in nociceptive processing. HighlightsCytokines are known to engage in complex interactions and regulate each other FL increases IL-1{beta} in DRG and DSC within 4h, but IL-1{beta} does not affect FL levels FL modulates capsaicin-induced Ca2+ influx via IL-1{beta}/IL-1R signalling in DRG neurons IL-1R inhibition delays or abolishes FL-induced mechanical hypersensitivity in vivo Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/648037v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@11cfa96org.highwire.dtl.DTLVardef@187ac2borg.highwire.dtl.DTLVardef@387234org.highwire.dtl.DTLVardef@1d1c058_HPS_FORMAT_FIGEXP M_FIG The timeline of the experimental design and the graphical abstract were created with BioRender.com C_FIG

neuroscience↗

bioRxiv2025

Functional Equivalence of the Proneural Genes Neurog1 and Neurog2 in the Developing Dorsal Root Ganglia Highlights the Importance of Timing of Neurogenesis in Biasing Somatosensory Precursor Fates

Distinct subfamilies of proneural bHLH transcription factors (TFs) control neurogenesis and influence neuronal fate specification throughout the developing nervous system. While members of different subfamilies generally display divergent expression and functions, those within the same subfamily are often co-expressed, raising questions about their respective roles. Here, we assess the functional equivalence of the two paralogous proneural TFs Neurog1 and Neurog2, focusing on neurons of the dorsal root ganglia (DRG) which underlie our ability to process somatosensory information. During development, distinct classes of DRG neurons -classified as mechano/proprioceptors or thermo/nociceptors-are generated during two successive neurogenic phases, which are respectively controlled by Neurog2 and Neurog1, in line with their dynamic and complementary spatiotemporal expression patterns. Therefore, in this system, each TF appears to play unique roles in regulating neurogenesis and specifying distinct neuronal identities. Yet, using a gene replacement strategy in vivo, we show that, despite subtle divergences masked by dose-compensation effects, Neurog1 and Neurog2 are essentially functionally interchangeable in all aspects of DRG development, indicating that their apparent functional discrepancies primarily stem from divergent evolution of their gene regulatory regions, rather than of their respective biochemical properties. Notably, we definitively establish that neither TF directly specifies specific somatosensory neuron identities. This result, combined with : (i) a new series of birth-dating experiments supporting that most mechano/proprioceptive and thermo/nociceptive subtypes are predominantly born during successive time-windows; and (ii) analyses of complementary transgenic mouse models in which opposite temporal shifts of neurogenesis -either delayed onset or premature arrest-have predictable opposite impacts on their DRG content, highlight that the fate choice of somatosensory precursors toward the mechano/proprioceptive or thermo/nociceptive lineages critically depends on the timing of their birth.

developmental biology↗

bioRxiv2022

E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE PROTEIN TRANSLATION FIDELITY DURING NEURONAL DEVELOPMENT

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pathogenesis. We identified the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensured proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlighted a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

developmental biology↗

bioRxiv2019

Cerebellar dopamine D2 receptors regulate preference for social novelty

The cerebellum, a primary center involved in the control of sensorimotor tasks, also contributes to higher cognitive functions including reward, emotion and social interaction. The regulation of these behaviors has been largely ascribed to the monoaminergic system in limbic regions. However, the contribution of cerebellar dopamine signaling in the modulation of these functions remains largely unknown due to the lack of precise characterization of cerebellar dopaminoceptive neurons. By combining cell type-specific transcriptomic and histological analyses, 3D imaging and electrophysiology we demonstrate that cerebellar dopamine D2 receptors (D2R) in mice are preferentially expressed in Purkinje cells (PCs). While activation of D2R regulate synaptic efficacy onto PCs, their deletion or overexpression in PCs bidirectionally controls preference for social novelty without affecting motor functions. Altogether, these findings demonstrate novel D2Rs roles in PC function and causally link cerebellar D2R levels of expression to social behaviors.

neuroscience↗

bioRxiv2018

p75 Neurotrophin Receptor Regulates the Timing of the Maturation of Cortical Parvalbumin Cell Connectivity and Promotes Ocular Dominance Plasticity in Adult Visual Cortex.

By virtue of their extensive axonal arborisation and perisomatic synaptic targeting, cortical inhibitory Parvalbumin (PV) cells strongly regulate principal cell output and plasticity. An interesting aspect of PV cell connectivity is its prolonged maturation time course, which is completed only by end of adolescence. The p75 neurotrophin receptor (p75NTR) regulates a wide range of cellular function, including apoptosis, neuronal process remodeling and synaptic plasticity, however its role on cortical circuit development is still not well understood, mainly because localizing p75NTR expression with cellular and temporal resolution has, so far, been challenging.\n\nUsing RNAscope and a modified version of the Proximity Ligation Assay (PLA), we show that p75NTR mRNA and protein are expressed in cortical PV cells in the postnatal and adult brain. Further, p75NTR expression in PV cells decreases between postnatal day (P)14 and P26, at a time when PV cell synapse numbers increase dramatically. Conditional knockout of p75NTR in single PV neurons in cortical organotypic cultures and in PV cell networks in vivo leads to precocious formation of PV cell perisomatic innervation and perineural nets around PV cell somata, suggesting that p75NTR expression controls the timing of the maturation of PV cell connectivity in the adolescent cortex.\n\nRemarkably, we found that p75NTR is still expressed, albeit at low level, in PV cells in adult cortex. Interestingly, activation of p75NTR onto PV cells in adult visual cortex in vivo is sufficient to destabilize their connectivity and to reintroduce juvenile-like cortical plasticity following monocular deprivation. Altogether, our results show that p75NTR activation dynamically regulates PV cell connectivity, and represents a novel tool to foster brain plasticity in adults.

neuroscience↗