Biology subjects

Masin, L.

Publications and source records attributed to Masin, L..

11 recordsLinked to original sources

bioRxiv2026

An evolutionarily conserved interferon-responsive oligodendroglial state emerges during white matter aging

White matter dysfunction is a hallmark of brain aging and often precedes overt neurodegeneration, yet the cellular alterations connecting aging to white matter dysfunction remain poorly understood. Here, we establish the killifish optic nerve as a translational model of white matter aging by integrating transcriptomic, histological and ultrastructural analyses. This tissue recapitulates key molecular and structural features of mammalian white matter aging, including the depletion of oligodendroglial progenitor cells, metabolic dysfunction and reduced myelin thickness. Intriguingly, aging is also associated with the emergence of an interferon-responsive oligodendroglial state. This state is characterized by interferon response and antigen presentation programs that closely resemble those of pathology-associated oligodendroglia described in murine models of central nervous system disease. Our findings identify oligodendroglial dysfunction as a central feature of white matter aging and suggest that this age-associated oligodendroglial state emerges before overt neurodegeneration, providing a potential cellular link between aging and neurodegenerative diseases.

neuroscience↗

bioRxiv2026

Repressed mTORC1 signaling and transient dendritic pruning support axonal regeneration

Dendrite degeneration is an early pathological feature following axonal damage, yet its role during successful axonal regeneration remains poorly understood. Using sparse labeling of retinal ganglion cells in adult zebrafish, we show that axonal regeneration is accompanied by a transient phase of dendritic pruning following optic nerve crush. Dendritic pruning occurs during axon elongation and is reversed after brain reinnervation. Although insulin-mTOR signaling is rapidly upregulated immediately after injury, it is subsequently suppressed, coinciding with dendritic pruning and sustained axonal growth. Prolonging mTOR activation through insulin treatment or direct pathway stimulation reduces dendritic pruning in an mTORC1-dependent manner but severely delays axonal regrowth. Together, these findings identify dendritic remodeling as a key temporally regulated component of successful axonal regeneration and reveal a functional trade-off between dendritic preservation and axon regrowth. This balance may represent a critical constraint for promoting CNS repair in mammals.

neuroscience↗

bioRxiv2025

Differential retinal ganglion cell resilience to optic nerve injury across vertebrate species

Optic neuropathies comprise a diverse group of disorders that ultimately lead to retinal ganglion cell (RGC) degeneration. Despite varying etiologies, these conditions share a conserved pathological progression: axonal damage in the optic nerve triggers progressive RGC degeneration. Understanding species-specific differences in neuronal resilience is critical for identifying key survival mechanisms and potential neuroprotective targets. In this study, we compare RGC densities and survival rates following optic nerve crush (ONC) in three vertebrate models--mice, zebrafish, and killifish--under standardized experimental conditions. Transcriptomic analysis confirmed that, similar to RBPMS in mice, Rbpms2 serves as a pan-RGC marker in zebrafish and killifish. Using these markers, we reveal significant species-specific differences in RGC density, with fish species exhibiting over a five-fold higher density than mice at equivalent life stage. Killifish also show an age-dependent decline in RGC density. Furthermore, we identify distinct injury responses across species: mice undergo rapid degeneration, losing [~]80% of their RGCs by day 14 after ONC; zebrafish maintain full RGC retention for two weeks before experiencing a loss of [~]12%; and killifish display a biphasic response to ONC, with young adults retaining two-thirds of their RGCs by day 21, while older fish exhibit a more pronounced second wave of RGC loss, ultimately preserving just over half of their RGCs by 21 days after injury. These findings highlight fundamental differences in neuroprotective capacity among species, providing a comparative framework to uncover molecular mechanisms governing RGC survival and to identify therapeutic strategies for treating optic neuropathies and neurodegeneration across diverse pathologies.

neuroscience↗

bioRxiv2025

Predicting the Regenerative Potential of Retinal Ganglion Cells Based on Developmental Growth Trajectories

Retinal ganglion cells in the mammalian central nervous system fail to regenerate following injury, with the capacity to survive and regrow varying by cell type. This variability may be linked to differences in developmental programs that overlap with the genetic pathways that mediate regeneration. To explore this correlation, we compared the structural changes in mouse retinal ganglion cells during development with those occurring after axonal injury. The dendritic trees of over 1,000 ganglion cells were reconstructed at different developmental stages, revealing that each cell type follows a distinct timeline. ON-sustained (sON) cells reach maturity by P14, whereas ON-transient (tON) cells achieve their maximum dendritic size by P10. Modeling of the dendritic changes indicate that while sON and tON follow similar growth programs the onset of growth was later in sON. After optic nerve crush, the remodeling of dendritic architecture differed between the two cell-types. sON cells exhibited rapid dendritic shrinkage, while tON cells shrank more gradually with changes in branching features. Following injury, sON cells reverted to an earlier developmental state than tON cells. In addition, after co-deletion of PTEN and SOC3, neurons appeared to regress further back in developmental time. Our results provide evidence that a ganglion cells resilience to injury and regenerative potential is predicted by its maturation timeline. Understanding these intrinsic differences could inform targeted neuroprotective interventions.

neuroscience↗

bioRxiv2025

Successful axonal regeneration is driven by evolutionarily conserved metabolic reprogramming

Unlike mammals, zebrafish can regrow axons after injury and restore circuit function in the central nervous system (CNS). Mitochondria have been identified as key players in this process, but how different metabolic pathways work together to sustain regeneration remains unclear. Using RNA sequencing of adult zebrafish retinal ganglion cells after optic nerve crush injury, we found that oxidative phosphorylation is downregulated during axonal regrowth. Simultaneously, the thioredoxin antioxidant system was upregulated, likely to limit oxidative damage. Additionally, we observed an integrated upregulation of glycolysis and the pentose phosphate pathway during the initial regrowth phases, possibly to provide energy and supplying NADPH for biosynthesis and antioxidant responses. We show that this metabolic reprogramming is evolutionarily conserved, as a comparable one occurs in the pro-regenerative mammalian Pten and Socs3 co-deletion model. Inhibiting glycolysis and thioredoxin in zebrafish impairs axonal regrowth, suggesting that targeting these pathways could enhance CNS regeneration in mammals.

neuroscience↗

bioRxiv2024

Age-related dysregulation of the retinal transcriptome in African turquoise killifish

Age-related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short-lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single-cell RNA-sequencing (scRNA-seq) of three age groups (6-, 12-, and 18-week-old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age-related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterised, confirming the presence of all typical vertebrate retinal cell types. Data integration from age-matched samples between the bulk and scRNA-seq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasises the value of the fast-ageing killifish in elucidating molecular signatures in age-associated retinal disease and vision decline. This study contributes to the understanding of how age-related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age-related pathologies. HighlightsO_LIThe aged killifish retina displays several ageing hallmarks, such as oxidative stress, gliosis and inflammageing, at the transcriptome level. C_LIO_LIRisk genes for neurodegenerative disorders show dysregulation in the old killifish retina. C_LIO_LIAll vertebrate retinal cell types are present in the killifish retina. C_LIO_LITranscriptional dysregulation in the aged killifish retina is observed across cell types. C_LI

neuroscience↗

bioRxiv2024

Local glycolysis supports injury-induced axonal regeneration

Successful axonal regeneration following injury requires the effective allocation of energy. Mitochondria play a pivotal role, accumulating at the tips of growing axons to fuel regeneration. However, how axons withstand the initial disruption in mitochondrial energy production caused by the injury, and subsequently initiate regrowth is poorly understood. Using retinal cultures in a multicompartment microfluidic device, we observed increased regrowth and enhanced mitochondrial trafficking in the axons of retinal ganglion cells with the deletion of both Pten and Socs3. While wild-type axons relied on mitochondrial metabolism, after injury, in the absence of Pten and Socs3, energy production was demonstrated to be supported by local glycolysis. Slowing down glycolysis in these axons impaired both regrowth and energy production. Together, these observations reveal that glycolytic ATP, combined with sustained mitochondrial transport, is essential for injury-induced axonal regrowth, providing new insights into the metabolic underpinnings of axonal regeneration.

neuroscience↗

bioRxiv2024

Altered Socio-Affective Communication and Amygdala Development in mice with Protocadherin10-deficient Interneurons

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviors. The cell adhesion molecule Protocadherin10 (Pcdh10) has been implicated in the etiology of ASD. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and has been linked to neural circuit formation. Here, we show strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex of the amygdala at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the basolateral complex at perinatal stages and genes linked to vocalization behavior were enriched in Pcdh10- expressing neurons in adult mice. To further investigate the involvement of Pcdh10 in neurodevelopment with relevance to ASD, and to assess the functional and behavioral consequences of loss of Pcdh10 in basolateral amygdala interneurons, we combined a ubiquitous and a conditional Pcdh10 knockout mouse model. Conditional knockout of Pcdh10 reduced the number of interneurons in the basolateral complex. Both models exhibited altered developmental trajectories of socio-affective communication through isolation-induced ultrasonic vocalizations in neonatal pups, characterized by increased emission rates in heterozygous pups. Furthermore, acoustic call features were affected and heterozygous conditional knockout pups emitted calls characterized by reduced peak frequencies but increased frequency modulation. Additionally, we identified distinct clusters of call subtypes with specific developmental trajectories, suggesting the vocalization repertoire is extensive and dynamic during early life. The nuanced alterations in socio-affective communication at the level of call emission rates, acoustic call features, and clustering of call subtypes were primarily seen in heterozygous pups of the conditional knockout and less prominent in the ubiquitous Pcdh10 knockout, suggesting that changes in anxiety levels associated with Gsh2-lineage interneurons might drive the observed behavioral effects. Together, this demonstrates that loss of Pcdh10 specifically in interneurons contributes to behavioral alterations in socio-affective communication with relevance to ASD.

neuroscience↗

bioRxiv2022

Optimization of Whole Mount RNA multiplexed in situ Hybridization Chain Reaction with Immunohistochemistry, Clearing and Imaging to visualize octopus neurogenesis

Gene expression analysis has been instrumental to understand the function of key factors during embryonic development of many species. Marker analysis is also used as a tool to investigate organ functioning and disease progression. As these processes happen in three dimensions, the development of technologies that enable detection of gene expression in the whole organ or embryo is essential. Here, we describe an optimized protocol of whole mount multiplexed RNA in situ hybridization chain reaction version 3.0 (HCR v3.0) in combination with immunohistochemistry (IHC), followed by fructose-glycerol clearing and light sheet fluorescence microscopy (LSFM) imaging on whole-mount Octopus vulgaris embryos. We developed a code to automate probe design which can be applied for designing HCR v3.0 type probe pairs for fluorescent in situ mRNA visualization. As proof of concept, neuronal (Ov-elav) and glial (Ov-apolpp) markers were used for multiplexed HCR v3.0. Neural progenitor (Ov-ascl1) and precursor (Ov-neuroD) markers were combined with an immunostaining for phosphorylated-histone H3, a marker for mitosis. After comparing several tissue clearing methods, fructose-glycerol clearing was found optimal in preserving the fluorescent signal of HCR v3.0. The expression that was observed in whole-mount octopus embryos matched with the previous expression data gathered from paraffin-embedded transverse sections. Three-dimensional reconstruction revealed additional spatial organization that had not been discovered using two-dimensional methods.

developmental biology↗

bioRxiv2020

The AppNL-G-F mouse retina is a site for preclinical Alzheimer's disease diagnosis and research

In this study, we report the results of a comprehensive phenotyping of the retina of the AppNL-G-F mouse. We demonstrate that soluble A{beta} accumulation is present in the retina of these mice early in life and progresses to A{beta} plaque formation by midlife. This rising A{beta} burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology. Electrophysiological recordings reveal signs of neuronal dysfunction yet no overt neurodegeneration was observed and visual performance outcomes were unaffected in the AppNL-G-F mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal A{beta}, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the AppNL-G-F retina mimics the early, preclinical stages of AD, and, together with retinal imaging techniques, offers unique opportunities for drug discovery and fundamental research into preclinical AD.

neuroscience↗

bioRxiv2018

In Troyer Syndrome Spartin loss induces Complex I impairments and alters pyruvate metabolism

Growth delay and retardation are complex phenotypes which can results by a range of factors including genetics variants. We identified a novel homozygous frameshift mutation, c.892dupA, in SPART gene, in two brothers with short stature and psychomotor retardation, born from healthy consanguineous parents. Mutations in SPART are the cause of Troyer syndrome, an autosomal recessive form of spastic paraplegia resulting in muscle weakness, short stature and cognitive defects. SPART encodes for Spartin, a protein with different cellular functions, such as endosomal trafficking and mitochondrial stability.\n\nWe evaluated the effects of Spartin loss by transiently silencing SPART in human neural stem cells (hNSCs) and by generating an SH-SY5Y cell line model carrying the c.892dupA mutation via CRISPR/Cas9. In both models, we observed an altered neuronal growth and an increase in neurite outgrowth. In the SH-SY5Y cell line carrying the c.892dupA mutation, Spartin absence led to an altered distribution of mitochondria, and to a severe decrease in the NADH-dehydrogenase activity of mitochondrial Complex I. These impairments determined an energetic failure with a decrease in ATP synthesis due to a halt in mitochondrial oxidative phosphorylation, increased reactive oxygen species production, and alteration in intracellular Ca2+ homeostasis. Transient re-expression of Spartin in mutant cells restored an intracellular Ca2+ level. Mutant cells presented a significant increase in extracellular pyruvate, which may result from increased glycolysis due to impaired Complex I activity. Consistently, Spartin loss led to an over-activation of Signal Transducer and Activator of Transcription 3 (STAT3) factor, a key regulator of glycolysis.\n\nThese data demonstrate that Spartin loss leads to a profound bioenergetics imbalance with defective OXPHOS activity, and this altered metabolism might underlie Troyer syndrome and neurodevelopmental delays.

cell biology↗