Biology subjects

Senovilla-Ganzo, R.

Publications and source records attributed to Senovilla-Ganzo, R..

8 recordsLinked to original sources

bioRxiv2025

PKC-dependent MYRF dysregulation links Aβ pathology to oligodendrocyte, myelin and cognitive alterations in Alzheimer's disease

Alzheimers disease (AD) is characterized not only by neuronal loss and synaptic dysfunction but also by emerging evidence of oligodendrocyte and myelin pathology. Amyloid-{beta} (A{beta}), a hallmark of AD, disrupts oligodendrocyte homeostasis through mechanisms that remain poorly understood. Here, we investigated the role of the myelin regulatory factor (MYRF), a transcription factor essential for oligodendrocyte maturation, in AD-related glial dysfunction. Using the 3xTg-AD mouse model, we observed aberrantly induced maturation dynamics and reduced oligodendrocyte lineage cell density at 12 months in the dentate gyrus, accompanied by increased MYRF expression. Interestingly, sustained MYRF overexpression was found to be toxic for oligodendrocytes in vitro. Moreover, in vitro and in vivo experiments further demonstrated that A{beta} exposure elevates MYRF protein levels and enhances its transcriptional activity, pointing to post-translational regulation. Mechanistically, A{beta} impaired GSK3-dependent phosphorylation and Fbxw7-mediated ubiquitination of MYRF, prolonging N-MYRF stability, an effect prevented by PKC inhibition in vitro. Intracerebroventricular infusion of PKC inhibitor Go6983 normalized MYRF levels, restored oligodendrocyte populations and myelin integrity, and improved hippocampal-dependent spatial learning in 3xTg-AD mice, with locomotor activity and anxiety-like behavior remaining unaffected. Together, these findings identify MYRF dysregulation as a mechanistic link between A{beta}/PKC signaling and oligodendrocyte pathology, and highlight PKC inhibition as a potential strategy to restore oligodendroglial function and cognition in AD.

neuroscience↗

bioRxiv2025

Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

Early immune perturbations increase the risk of neurodegenerative and neurodevelopmental disorders, yet the mechanisms underlying the maturation of microglia, the resident immune cells of the brain parenchyma, remain poorly defined. Specifically, how proliferation, morphological differentiation, and phagocytosis are coordinated among microglia progenitors as they colonize the embryonic brain remains unclear. Here, we combined mathematical modeling with spatiotemporal analyses of the murine hippocampus and cerebellum from postnatal day 2 (P2) to P60 to reconstruct the trajectory of microglial development. We identified a proliferative-to-quiescent (P/Q) switch around P3/P4 that preceded the acquisition of morphological complexity and efficient phagocytosis and was accompanied by coordinated shifts in cell-cycle dynamics and metabolic state. Strikingly, this P/Q switch was recapitulated in repopulation contexts in mice and in the human fetal brain, where later stages displayed enhanced phagocytic function coupled to reduced proliferation. Perturbing the proliferative phase through pharmacological or genetic disruption of CSF1R signaling impaired subsequent microglial complexity and phagocytosis efficiency, revealing an unexpected reliance of phagocytosis on proliferation-driven colonization. Finally, we show that microglia stepwise maturation during development is associated with chromatin remodeling and driven by the epigenetic regulator Ikaros. Together, these findings uncover the sequential milestones of microglial development, revealing a potential period of early vulnerability and establishing an unexpected linkage between proliferation and phagocytosis essential to understanding how these processes are coordinated in neurodegenerative disorders.

neuroscience↗

bioRxiv2025

A dual genetic constraint underlies the conservation of early brains in vertebrates.

As the body plan, the embryonic brain bauplan reflects the shared features of vertebrate brains. Yet, disagreements among sparse histogenetic frameworks have undermined the bauplans power to trace homologies. Here, we generate and integrate five vertebrate single-cell multi-omic atlases of early embryonic brains, revealing a conserved cellular blueprint that defines equivalent progenitor domains across species. Our cellular neuromeric model provides an unified and unbiased framework for the vertebrate brain bauplan and revises the regionalisation of the prosencephalon, refining its molecular boundaries and developmental relationships. Furthermore, cross-species gene-network analyses expose regulatory complexity beyond classical neuromeric patterning, resolving networks into modules aligned with regional cell types or cell class (progenitor/neuron). Evolutionarily, two main developmental constraints emerge: brain bauplan genes, early essential for regional identity, and pleiotropic stemness gene modules, indispensable across all proliferating cells. In turn, later development displays tissue-specific and less essential modules, explaining its rapid divergence into species-specific features. Together, these findings reveal a dual evolutionary constraint--neuromeric identity and pleiotropic stemness--that underlies the conservation of early vertebrate brains. This duality explains how deeply conserved regulatory architectures coexist with evolutionary flexibility to develop into the immense diversity of vertebrate nervous systems. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=77 SRC="FIGDIR/small/684766v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@a337a2org.highwire.dtl.DTLVardef@19987adorg.highwire.dtl.DTLVardef@9a9394org.highwire.dtl.DTLVardef@4ef279_HPS_FORMAT_FIGEXP M_FIG C_FIG

evolutionary biology↗

bioRxiv2024

Evolutionary convergence of sensory circuits in the pallium of amniotes

The amniote pallium contains sensory circuits structurally and functionally equivalent, yet their evolutionary relationship remains unresolved. Our study employs birthdating analysis, single-cell RNA and spatial transcriptomics, and mathematical modeling to compare the development and evolution of known pallial circuits across birds (chick), lizards (gecko) and mammals (mouse). We reveal that neurons within these circuits stations are generated at varying developmental times and brain regions across species, and found an early developmental divergence in the transcriptomic progression of glutamatergic neurons. Together, we show divergent developmental and evolutionary trajectories in the pallial cell types of sauropsids and mammals. Our research highlights significant differences in circuit construction rules among species and pallial regions. Interestingly, despite these developmental distinctions, the sensory circuits in birds and mammals appear functionally similar, which suggest the convergence of high-order sensory processing across amniote lineages.

developmental biology↗

bioRxiv2024

Developmental origins and evolution of pallial cell types and structures in birds

The advanced cognitive abilities of birds rival those of mammals and have been attributed to evolutionary innovations in the pallium. However, a comprehensive cellular characterization of this brain region in birds has been lacking. We scrutinized the structures, cell types and evolutionary origins of the avian pallium based on single-cell and spatial transcriptomics atlases for the adult and developing chicken, and comparisons to corresponding data from mammals and non-avian reptiles. We found that the avian pallium shares most inhibitory neuron types with other amniotes. While excitatory neuron repertoires in the (medial) hippocampal formation show high conservation, they substantially diverged in other pallial regions during avian evolution, defining novel structures like the avian-specific (dorsal) hyperpallium, whose neuronal gene expression identities partly converge during late development with those of the (ventral) nidopallium. Our work also unveils the evolutionary relationships of pallial structures across amniotes, like the previously unknown homology between avian (lateral) mesopallial and mammalian deep layer cortical neurons. One-Sentence SummaryAn avian neural cell type atlas illuminates the developmental origins and evolution of the amniote pallium.

evolutionary biology↗

bioRxiv2024

Amyloid-beta increases MBP and MOBP translation in oligodendrocytes through dysregulation of hnRNP A2 dependent RNA dynamics

Oligodendrocyte dysfunction, myelin degeneration, and white matter structural alterations are critical events in Alzheimers disease (AD) that contribute to cognitive decline. A key hallmark of AD, A{beta} oligomers, disrupt oligodendrocyte and myelin homeostasis, but a comprehensive global analysis of the mechanisms involved is lacking. Here, transcriptomic profiling of A{beta}-exposed oligodendrocytes revealed widespread gene expression changes, particularly affecting pathways related to RNA localisation. Among the genes identified, we focused on Hnrnpa2/b1, the gene encoding the hnRNP A2 protein, which is essential for RNA transport and translation of myelin proteins. We confirmed aberrant upregulation of hnRNP A2 in hippocampal oligodendrocytes from post-mortem human brains of early-stage AD patients, A{beta}-injected mouse hippocampi and A{beta}-treated disrupting cells in vitro. RIP-seq analysis of the hnRNP A2 interactome revealed attenuated interactions with Hnrnpk and Hnrnpa2/b1, while interactions with Mbp and Mobp were enriched, suggesting changes in RNA metabolism of molecules associated with mRNA transport of myelin proteins. A{beta} increased the total number and dynamics of mRNA-containing granules, facilitating local translation of the myelin proteins MBP and MOBP and attenuating Ca2+ signalling. These findings suggest that A{beta} oligomers disrupt RNA metabolism mechanisms crucial for oligodendrocyte myelination through dysregulation of hnRNP A2 and myelin protein levels, potentially affecting oligodendroglia Ca2+ homeostasis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/590214v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@19e046eorg.highwire.dtl.DTLVardef@134f15corg.highwire.dtl.DTLVardef@d1f8aaorg.highwire.dtl.DTLVardef@11c97af_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG

molecular biology↗

bioRxiv2024

Hippocampal reactive neural stem cells are able to phagocytose and have an immunological molecular signature

Hippocampal neural stem cells (NSCs) are the drivers of neurogenesis in the dentate gyrus (DG) of most mammals including humans. During neuronal hyperactivity NSCs become reactive NSCs (react-NSCs), characterized by their activation, morphological changes, and symmetric division, abandoning their neurogenic programme and transforming into reactive astrocytes. Here, using different pathological models that induce react-NSCs in the DG, we looked for novel features of react-NSCs both histologically and by total RNA sequencing. We report that in two pathological models were react-NSCs emerge (mesial temporal lobe epilepsy (MTLE) and traumatic brain injury (TBI)) react-NSCs are capable of phagocytosis of dead cells, a typical immunological function carried out mainly by microglia in the brain. Importantly, MTLE-induced react-NSCs show phagocytic function in tissue and a predominantly immunological molecular signature, with a broad upregulation of phagocytosis-related gene expression. Our results describe a new function of react-NSCs as phagocytic and immunologically active cells in the hippocampal neurogenic niche.

neuroscience↗

bioRxiv2023

BirthSeq, a new method to isolate and analyze dated cells from any tissue in vertebrates

Embryonic development is a complex and dynamic process that unfolds over time and involves the production of increasing numbers of cells, as well as the diversification of different cell types. The impact of developmental time on the formation of the central nervous system is well-documented, with evidence showing that time plays a critical role in establishing the identity of neuronal subtypes. However, the study of how time translates into genetic instructions driving cell fate is limited by the scarcity of suitable experimental tools. We introduce BirthSeq, a new method for isolating and analyzing cells based on their birth date. This innovative technique allows for in vivo labeling of cells, isolation via FACS, and analysis using high-throughput techniques. We demonstrate the effectiveness of BirthSeq for single-cell RNA sequencing and novel spatially resolved transcriptomic approaches in brain development across three vertebrate species (mouse, chick, and gecko). Overall, BirthSeq provides a versatile tool for studying any tissue in any vertebrate organism, helping to fill the necessity in developmental biology research by targeting cells and their temporal cues. SUMMARY STATEMENTBirthSeq allows the isolation and investigation of alive cells according to their birthdate, in any kind of tissue and vertebrate species.

developmental biology↗