Biology subjects

Lopez-Atalaya, J. P.

Publications and source records attributed to Lopez-Atalaya, J. P..

12 recordsLinked to original sources

bioRxiv2026

Blade-dependent molecular identity and neurogenic potential in the adult dentate gyrus

The dentate gyrus (DG) is a key hippocampal gateway for cognition and emotion and a major site of adult neurogenesis, yet its organization along the transverse (suprapyramidal- infrapyramidal) axis remains poorly understood. Here, by integrating bulk RNA sequencing of microdissected mouse DG blades with spatial transcriptomics and single-nucleus RNA sequencing, we define the suprapyramidal and infrapyramidal blades (SB and IB) as distinct molecular compartments characterized by anterior-posterior-dependent gene expression programs. Functionally, the SB exhibits enhanced neurogenic activity, particularly in the anterior DG, including increased progenitor proliferation and neuronal differentiation, whereas the IB contains a larger pool of quiescent neural stem cells. Together, these findings reveal molecular and functional specialization along both transverse and longitudinal axes of the DG and provide a framework for interrogating hippocampal subregional organization in health and disease.

neuroscience↗

bioRxiv2025

Metabolic and transcriptional adaptations to phagocytosis in microglia sustain their functionality and regenerative properties

Phagocytosis of apoptotic cells, or efferocytosis, is a tightly regulated process that ensures tissue homeostasis and prevents mounting inflammatory responses. In the brain parenchyma, it is executed by microglia, which are encumbered by large numbers of apoptotic debris generated during development, in adult neurogenic niches, aging, and brain diseases. Emerging evidence suggest that phagocytosis is not limited to garbage disposal, but triggers adaptations in the phagocytes that may have a functional impact. To test it we developed an in vivo model of superphagocytosis induced by low cranial irradiation (LCI, 2Gy) that specifically induced apoptosis in the neurogenic niche of the adult hippocampus, synchronizing microglia in a phagocytic state within 6h and leading to full clearance by 24h. Single cell RNA sequencing and metabolomics revealed an unexpected oxidative stress in post-phagocytic microglia, accompanied by catabolic shutdown, mitochondrial remodeling, increased expression of galectin 3, and production of polyamines that led to cell death and compensatory proliferation. To test whether these changes impaired subsequent microglial phagocytosis, we used a glioblastoma model treated with sequential irradiation to induce tumor cell apoptosis. The phagocytosis efficiency of tumor-associated microglia/macrophages was comparable in the first and second apoptotic challenge, suggesting that the metabolic remodeling induced by phagocytosis was adaptive and destined to sustain their functionality. Finally, we assessed the functional impact of post-phagocytosis adaptations using galectin 3 deficient mice under LCI. We found that the recovery of the neurogenic niche after LCI strongly depended on galectin 3, demonstrating the regenerative capacity of post-phagocytic microglia. Overall, our data unveils the complexity of post-phagocytosis adaptations in microglia, underscoring their unexplored therapeutic potential in brain disorders.

neuroscience↗

bioRxiv2025

MIF-induced CD74+ microglia/macrophages are clinically relevant disease-associated subpopulations in brain metastasis and other CNS disorders

The upregulation of CD74, a chaperone involved in MHC-II antigen processing 1,2, has been broadly reported in virtually all brain disorders analyzed by single-cell RNA sequencing 3-6. However, its expression is usually interpreted as indicative of antigen presentation. In parallel, CD74 expression has also been described in cancer cells across multiple tumor types, but interestingly in glioma its expression has been mainly identified in the microenvironment. However, the functional contribution of CD74 to disease progression in the brain, and specifically in secondary brain tumors, has not been directly addressed. Here we described that, in contrast to what it has been assumed, the presence of CD74+ microglia/macrophages, which is induced by increased levels of interferon gamma in the brain affected by metastases, does not relate to its canonical pathway. Instead, CD74s alternative function as cytokine receptor is pivotal. Rewired by increasing levels of its ligand MIF, produced by proliferating cancer cells, the CD74 receptor, upon binding to this ligand, translocates to the nucleus activating a NF-{kappa}B-dependent program promoting metastasis progression. A brain metastasis-associated CD74 signature involves a more aggressive progression of the local disease in patients, while it has no clinical correlation with the matched primary tumor. Furthermore, we identified the CD74+ myeloid population in additional brain disorders including Alzheimers disease and multiple sclerosis, which shared a pan-disease non-canonical signature with clinical relevance. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreases brain metastases in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. Our findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a novel vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders, guided by a non-invasive molecular strategy.

cancer biology↗

bioRxiv2025

Sex-dependent interferon signaling drives female-biased vulnerability in Alzheimer's disease

Alzheimers disease (AD) disproportionately affects women, yet the neurobiological mechanisms underlying this sex bias remain poorly understood. Here, we identify a sex-dependent activation of type I interferon (IFN-I) signaling as a contributor to this disparity. Transcriptomic profiling of brain from AD patients revealed selective enrichment of IFN-I pathway in females. This immune signature was mirrored in the APP/PS1 mouse model of AD, where females exhibited more pronounced amyloid accumulation, neuroinflammation, and neurodegeneration. Acute IFN-I activation reproduced pathological features of AD, whereas chronic IFN-I elevation in APP/PS1 mice aggravated disease progression. In contrast, pharmacological targeting of IFN-I response by inhibiting the cGAS-STING pathway in APP/PS1 female mice reduced neuropathological burden, and preserved cognitive performance. Together, these findings identify interferon signaling as a modifiable and sex-linked driver of AD pathology. Our study uncovers a critical neuroimmune mechanism contributing to female-biased vulnerability and highlights interferon modulation as a promising therapeutic strategy in AD.

neuroscience↗

bioRxiv2025

Early lineage divergence segregates sensory and non-sensory thalamic circuits

The thalamus integrates sensory, motor, and associative functions via distinct nuclei, yet the developmental principles driving their specification remains unclear. Here, we generate a spatiotemporal single-cell multiomic and spatial transcriptomic atlas of the embryonic mouse thalamus, combined with barcoding-based lineage tracing. We identify two major glutamatergic lineages--sensory and motor/associative--each governed by different gene regulatory programs and temporal dynamics. These lineages arise from spatially and molecularly isolated progenitors, revealing an early segregation of functional identities. Within the sensory lineage, we resolve two discrete trajectories leading to first-order visual and somatosensory neurons, both emerging from a shared higher-order default state. Using in silico predictions and in vivo perturbations, we identify Sp9 as a key regulator of visual thalamic fate. Together, our findings define the molecular architecture and developmental trajectories that underpin thalamic modality specification, providing a framework to understand how functional circuits emerge in the mammalian brain.

neuroscience↗

bioRxiv2024

A single dose of cocaine rewires the 3D genome structure of midbrain dopamine neurons

Midbrain dopamine neurons (DNs) respond to a first exposure to addictive drugs and play key roles in chronic drug usage1-3. As the synaptic and transcriptional changes that follow an acute cocaine exposure are mostly resolved within a few days4,5, the molecular changes that encode the long-term cellular memory of the exposure within DNs remain unknown. To investigate whether a single cocaine exposure induces long-term changes in the 3D genome structure of DNs, we applied Genome Architecture Mapping and single nucleus transcriptomic analyses in the mouse midbrain. We found extensive rewiring of 3D genome architecture at 24 hours past exposure which remains or worsens by 14 days, outlasting transcriptional responses. The cocaine-induced chromatin rewiring occurs at all genomic scales and affects genes with major roles in cocaine-induced synaptic changes. A single cocaine exposure triggers extensive long-lasting changes in chromatin condensation in post-synaptic and post-transcriptional regulatory genes, for example the unfolding of Rbfox1 which becomes most prominent 14 days post exposure. Finally, structurally remodeled genes are most expressed in a specific DN sub-type characterized by low expression of the dopamine auto-receptor Drd2, a key feature of highly cocaine-sensitive cells. These results reveal an important role for long-lasting 3D genome remodelling in the cellular memory of a single cocaine exposure, providing new hypotheses for understanding the inception of drug addiction and 3D genome plasticity.

genomics↗

bioRxiv2021

Sublayer- and cell-type-specific neurodegenerative transcriptional trajectories in hippocampal sclerosis

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type specific vulnerability, their progression and histopathological classification remain controversial. Here using single-cell electrophysiology in vivo and immediate early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rats and mice in vivo. Bulk tissue and single-nucleus expression profiling disclosed sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage-channels, synaptic signalling and cell adhesion molecules were deregulated by epilepsy differently across sublayers, while neurodegenerative signatures primarily involved superficial cells. Pseudotime analysis of gene expression in single-nuclei and in situ validation revealed separated trajectories from health to epilepsy across cell types, and identified a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate sublayer- and cell type-specific changes associated with selective CA1 neuronal damage contributing to progression of hippocampal sclerosis.

neuroscience↗

bioRxiv2020

Astrocytes and neurons share brain region-specific transcriptional signatures

Neuronal cell diversity is essential to endow distinct brain regions with specific functions. During development, progenitors within these regions are characterised by specific gene expression programs, contributing to the generation of diversity in postmitotic neurons and glia. While the region-specific molecular diversity of neurons and astrocytes is increasingly understood, whether these cells share region-specific programs remains unknown. Here, we show that in the neocortex and thalamus, neurons and astrocytes express shared region-specific transcriptional and epigenetic signatures. These signatures not only distinguish cells across brain regions but are also detected across substructures within regions, such as distinct thalamic nuclei, where clonal analysis revealed the existence of common nucleus-specific progenitors for neurons and glia. Consistent with their shared molecular signature, regional specificity was maintained following astrocyte-to-neuron reprogramming. A detailed understanding of these regional-specific signatures may thus inform strategies for future cell-based brain repair.

neuroscience↗

bioRxiv2020

Astrocyte to microglia cross-talk in acute and chronic neuroinflammation is shaped by SFRP1

Neuroinflammation is a common feature of many neurodegenerative diseases, which fosters a dysfunctional neuron-microglia-astrocyte crosstalk that, in turn, maintains microglial cells into a perniciously reactive state that often enhance neuronal damage. The molecular components that mediate this critical communication are however not fully explored. Here, we have asked whether Secreted-Frizzled-Related-Protein-1 (SFRP1), a multifunctional regulator of cell-to-cell communication, is part of the cellular crosstalk underlying neuroinflammation. We show that in mouse models of acute and chronic neuroinflammation, astrocyte-derived SFRP1 is sufficient to promote and sustain microglial activation, and thus a chronic inflammatory state. SFRP1 allows the upregulation of components of Hypoxia Induced Factors-dependent inflammatory pathway and, to a lower extent, of those downstream of the Nuclear Factor-kappaB. We thus propose that SFRP1 acts as a critical astrocyte to microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation present in several neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Neuronal identity is maintained in the adult brain through KAT3-dependent enhancer acetylation

Very little is known about the mechanisms responsible for maintaining cell identity in mature tissues. The paralogous type 3 lysine acetyltransferases (KAT3) CBP and p300 are both essential during development, but their specific functions in nondividing differentiated cells remains unclear. Here, we show that when both proteins are simultaneously knocked-out in excitatory neurons of the adult brain, the mice express a rapidly progressing neurological phenotype associated with reduced dendritic complexity and electrical activity, the transcriptional shutdown of neuronal genes, and a dramatic loss of H3K27 acetylation and pro-neural transcription factor binding at neuronal enhancers. The neurons lacking both KAT3 rapidly acquire a molecularly undefined fate with no sign of dedifferentiation, transdifferentiation or death. Restoring CBP expression or lysine acetylation reestablished neuronal-specific transcription. Our experiments demonstrate that KAT3 proteins act as fate-keepers in excitatory neurons and other cell types by jointly safeguarding chromatin acetylation levels at cell type-specific enhancers throughout life.

cell biology↗

bioRxiv2019

Zic2 abrogates an alternative Wnt signaling pathway to convert axon attraction into repulsion

Wnt signaling is involved in axon pathfinding during brain wiring but it is unknown how Wnt ligands promote attraction or repulsion. In addition, the participation of the canonical ({beta}catenin-dependent transcription) versus non-canonical ({beta}catenin-independent) Wnt pathways in this process remains controversial. Here we show that Wnt5a is expressed at the optic chiasm midline and promotes axon crossing by triggering an alternative Wnt pathway that depends on polarized accumulation of {beta}catenin at the axon terminal but does not activate the canonical pathway. Remarkably, this alternative pathway is silenced by the transcription factor Zic2 in the small subset of ipsilaterally projecting neurons. Zic2 directly regulates genes related to Wnt and Eph signaling that lead to global accumulation of {beta}catenin but triggers its asymmetric phosphorylation to facilitate the steering of the growth cone. This alternative Wnt pathway found in contralateral axons and its Zic2-mediated abrogation in ipsilateral neurons is likely operating in many other contexts requiring a two-way response to Wnt ligands.

developmental biology↗

bioRxiv2019

MIR3607 regulates cerebral cortex development via activation of Wnt/βCat signaling

The evolutionary expansion of the mammalian cerebral cortex is recapitulated during embryonic development in large mammals, but the underlying genetic mechanisms remain mostly unknown. Previous transcriptomic analyses of the developing ferret cortex identify candidate genes related to the expansion of germinal layers and cortex size. Here we focused on MIR3607, a microRNA differentially expressed between germinal layers of the large human and ferret cortex, not expressed in the small mouse cortex. Expression of MIR3607 in mouse embryos at E14.5 leads to increased progenitor cell proliferation. This is reflected in transcriptomic changes, which also reveal increased Wnt/{beta}Catenin signaling. Expression of MIR3607 at E12.5, when progenitor cells expand, causes amplification and severe delamination of apical progenitors, leading to rosette formation. This is rescued by co-expressing Adenomatous Polyposis Coli, inhibitor of canonical Wnt signaling. A similar phenotype is produced in human cerebral organoids. Our findings demonstrate that MIR3607 expands and delaminates apical progenitor cells via activating Wnt/{beta}Catenin, and suggest that a secondary loss of expression in mouse may underlie their reduction in cortex size during recent evolution.

developmental biology↗