Biology subjects

Motta, A.

Publications and source records attributed to Motta, A..

11 recordsLinked to original sources

bioRxiv2026

Multidimensional divergence supports parapatric speciation along an elevational gradient in ground-dwelling frogs on an oceanic island

Geographic isolation is a major driver of lineage divergence. However, strong ecological selection can promote reproductive isolation despite opportunities for gene flow in geographically continuous landscapes such as mountains. Here, we test whether ecological divergence across elevational gradients can promote speciation within a single mountain range. Integrating phylogenomic (ddRAD), morphological, and bioacoustic data, we test predictions of elevation-mediated parapatric speciation in Platymantis (Lahatnanguri) ground-dwelling frogs on Mindanao Island, Philippines. Phylogenomic analyses recovered an endemic radiation across neighboring mountain ranges and revealed a hierarchical pattern of diversification among three monophyletic lineages, with deeper divergence separating the mountain lineages Highland 1 and Highland 2 and more recent divergence occurring within a single mountain range. This topology identified a morphologically and acoustically distinct low-elevation lineage (<1,400 m a.s.l.) as closely related to the high-elevation Highland 1 lineage (>1,400 m a.s.l.), providing a natural test of divergence along an elevational gradient. The parapatric Lowland and Highland 1 lineages appear to have diverged relatively recently, as reflected in their shallow genome-wide differentiation, yet exhibit pronounced morphological and acoustic divergence. Population genomic analyses further recover discrete genomic clusters and no evidence of contemporary hybridization between the parapatric lineages, indicating independent evolutionary trajectories despite geographic continuity. Together, these findings are consistent with parapatric speciation along an elevational gradient and demonstrate how substantial phenotypic and reproductive-isolation divergence can accumulate despite limited genome-wide differentiation. More broadly, our results indicate that the exceptional biodiversity of oceanic archipelagos may arise not only from diversification among islands (and among mountains within islands) but also from lineage divergence along elevational gradients within mountains themselves. These empirical results support the biological plausibility of parapatric speciation within single mountain systems and highlight an underrecognized mechanism contributing to biodiversity in topographically complex oceanic archipelagos.

evolutionary biology↗

bioRxiv2026

Nanoparticle size governs engagement with myeloid cells and hitchhiking to hematopoietic organs in myeloproliferative neoplasms

Nanoparticle design principles contribute to desirable in vivo performance, including prolonged circulation, desirable biodistribution profiles, and tuned interactions with the immune system. The importance of these variables, although well-established in solid tumors, remains elusive in the context of hematological malignancies. Here, we investigated the influence of liposome size on biodistribution and cellular uptake within hematopoietic compartments - bone marrow (BM) and spleen - in JAK2V617F myeloproliferative neoplasms (MPN). A milli-fluidic manufacturing platform combined with a Design-of-Experiments (DoE) approach was used to generate small, medium, and large liposomes. Liposome uptake was assessed ex vivo using blood samples from healthy donors and MPN patients, followed by in vivo biodistribution studies in a transgenic JAK2V617F MPN mouse model. Organ-level accumulation was quantified using hybrid fluorescence / computed tomography (FLT/CT) imaging, while cellular uptake was evaluated via flow cytometry. Whole-body imaging revealed that increasing liposome size enhanced delivery to both the spleen and BM, with larger liposomes exhibiting the highest accumulation in both organs. Cellular analysis corroborated the in vivo observations, demonstrating that large liposomes are taken up to a greater extent by monocytes and granulocytes, in both spleen and BM. At late time-points post-injection, the liposomal accumulation was twice as high in the BM in comparison to the spleen and peripheral blood, highlighting the progressively elevated accumulation and retention in the BM, as opposed to the elimination phase nanoparticles undergo in clearance organs and circulation at these time-points. Of note, among BM mature myeloid cells, neutrophils were associated with a higher nanoparticle uptake than monocytes, highlighting their capability to phagocytose material in circulation and hitchhike it to malignant or inflamed regions. These findings demonstrate that continuous flow manufacturing procedures can swiftly produce nanoparticles with desirable characteristics that are essential for tuning the biodistribution towards hematopoietic organs and myeloid immune cells. By providing mechanistic insights into nanoparticle behavior within hematopoietic compartments, this work advances our understanding of nanomedicine in vivo performance and highlights particle size as a critical quality attribute that can be optimized and controlled to improve targeted delivery to myeloid cells in the treatment of hematological malignancies.

cancer biology↗

bioRxiv2025

Early endothelial activation at the blood-nerve barrier defines a hallmark of ALS

Vascular defects are common in Amyotrophic Lateral Sclerosis (ALS). The prevailing view is that breakdown of the blood-brain and blood-spinal cord barriers contributes to neurodegeneration. Here, we reveal that selective and early vulnerability of peripheral nerve endothelium --manifested as endothelial cell activation and interlinked blood-nerve barrier dysfunction-- constitutes a core feature of ALS pathogenesis, arising before vascular alterations in the central nervous system (CNS) and motor neuron pathology. Vascular changes in ALS patients have been largely studied in postmortem samples, limiting insight into their onset, causes, and pathogenic role. Surveying diagnostic motor nerve samples from ALS patients across clinical stages, we observed endothelial damage that preceded axonal loss and demyelination, marking vascular dysfunction as an early disease event. Similar ultrastructural abnormalities were detected in pre-symptomatic ALS mouse models (SOD1 and TARDBP mutants). Notably, endothelial cells became dysfunctional even when not carrying mutant TDP-43, indicating they respond to non-cell autonomous disease signals. Transcriptional, histological, and functional analyses revealed that these alterations were largely confined to peripheral nerves, while spinal cord vessels exhibited delayed and more focal changes. Single-cell sequencing identified ALS-susceptible endothelial cell subsets prone to a pro-inflammatory phenotype and impaired blood-nerve barrier function, increasing permeability via the transcellular route. These changes coincided with reactivity of nerve-resident macrophages and neutrophil infiltration. Neutrophil depletion attenuated endothelial activation and barrier leakiness, mitigating axonopathy in ALS mice. Our work unmasks the greater susceptibility of the peripheral nerve vasculature in ALS relative to the CNS. The early activation of peripheral nerve endothelium, combined with its potential reversibility, identifies a therapeutic window and suggests strategies for targeting the vascular-immune axis to protect the motor system.

neuroscience↗

bioRxiv2025

A neurovascular template guides the spatial and functional compartmentalization of the adrenal gland

The vasculature adapts to tissue demands, but whether it can instruct spatial tissue organization remains unclear. In the developing adrenal gland, we uncover a neurovascular mechanism that actively establishes and preserves compartment boundaries between cortex and medulla. Peripheral nerves secrete Semaphorin3C, signaling through PlexinD1 on endothelial cells to locally antagonize VEGF-driven angiogenesis from cortical cells, sculpting distinct vascular domains that guide hormone-producing cells to their correct territories. Disruption of this balance --via denervation or loss of Semaphorin3C-PlexinD1 signaling-- leads to ectopic vascularization of the medulla, which adopts a cortex-like vascular network. This vascular remodeling enables cortical cells invasion of medullary territories, blurring compartment boundaries and triggering a phagocytic macrophage response that reflects pathological hijacking of a postnatal morphogenesis program. Our findings reveal that region-specific vascular scaffolds, shaped by neurovascular cues, serve as instructive templates for organ architecture. Failure of neurovascular signaling can thus trigger a cascade of structural collapse that undermines tissue integrity and homeostasis, driving pathological remodeling.

developmental biology↗

bioRxiv2025

Connectomic analysis of astrocyte-synapse interactions in the cerebral cortex

Astrocytes, a main type of glia cells in the cortex, provide metabolic support to neurons, and their possible function as a synaptic partner has given rise to the notion of "tripartite" synapses, suggesting a contribution to neuronal computations. For astrocytes to serve such purposes, the interactions with synapses in neuronal circuits require a level of specificity beyond overall synaptic support. A systematic mapping of the astrocyte-connectome relationship would enable the testing of these hypotheses - such analysis is however still lacking, in particular for circuits in the cerebral cortex. Here, utilizing previously published connectomic data of more than 200,000 synapses, we systematically analyzed the spatial relation between astrocytes and synapses in mouse somatosensory cortex. We developed a quantitative assessment of astrocyte-synapse proximity, finding that only 22.7% of synapses are contacted by astrocytic processes for more than 50% of their synaptic circumference. This non-ubiquitous astrocytic attachment would render astrocyte-synapse specificity plausible. Astrocytic coverage depended strongly on synapse types, with thalamocortical shaft synapses being the most covered by astrocytic processes. We furthermore observed a strong dependence of astrocytic synaptic coverage on synapse size, which was exclusive for excitatory spine synapses. We then investigated the possible relation of astrocytic synaptic coverage to neuronal activity and synaptic plasticity, finding ultrastructural evidence for substantially reduced astrocytic support at synapses consistent with long-term depression, but not for astrocytic coverage dependence on baseline neuronal presynaptic activity. Together, our data demonstrate a high level of specificity of astrocyte-synapse interactions for particular synaptic types. They indicate the potential relevance of astrocytic coverage for synapse stability, in particular for large synapses, suggesting a contribution to long-term maintenance of learned synaptic states. These methods will allow a systematic testing of hypotheses about glial-neuronal interaction in various brain regions, disease models and species including human.

neuroscience↗

bioRxiv2024

Connectomic reconstruction of a cortical column

The cerebral cortex of mammals has long been proposed to comprise unit-modules, so-called cortical columns. The detailed synaptic-level circuitry of such a neuronal network of about 104 neurons is still unknown. Here, using 3-dimensional electron microscopy, AI-based image processing and automated proofreading, we report the connectomic reconstruction of a defined cortical column in mouse barrel cortex. The cortical column appears as a structural feature in the connectome, without need for geometrical or morphological landmarks. We then used the connectome for definition of neuronal cell types in the column, to determine intracolumnar circuit modules, analyze the logic of inhibitory circuits, investigate the circuits for combination of bottom-up and top-down signals in the column and the specificity of bottom-up and top-down cortical input, search for higher-order circuit structure within homogeneous neuronal populations, and estimate the degree and symmetry of Hebbian learning in the various connection types. With this, we provide a first column-level connectomic description of the cerebral cortex, the likely substrate for a synaptic-level mechanistic understanding of sensory-conceptual integration and learning.

neuroscience↗

bioRxiv2024

Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

IntroductionThe brain-related phenotypes observed in 22q11.2 deletion syndrome (22q11.2DS) are highly variable and their origin is poorly understood. Changes in brain metabolism may cause or contribute to the phenotypes, given that many of the deleted genes (approx. 10%) are implicated in metabolic processes, but this is currently unknown. It is clearly important to address this knowledge gap, but in humans, the primary material required for studying brain metabolism is inaccessible. For this reason, we sought to address the issue using two mouse models of 22q11.2DS. MethodsWe used three independent approaches to investigate brain metabolism in young adult mice, namely, mass spectrometry, nuclear magnetic resonance spectroscopy and transcriptomics. We selected to study primarily Tbx1 single gene mutants because it is the primary candidate disease gene. We then confirmed key findings in the multi-gene deletion mutant Df1/+. ResultsWe found that Tbx1 mutants have alterations of specific brain metabolites, including methylmalonic acid, which is highly brain-toxic, as well as a more general metabolomic imbalance. We provide transcriptomic evidence of an interaction genotype-vB12 treatment, and behavioural evidence of a response to vB12 treatment, which rescued some of the behavioural anomaly observed in Tbx1 mutants. We conclude that Tbx1 haploinsufficiency causes extensive brain metabolic anomalies, which are partially responsive to vB12 treatment. We suggest that alterations of glutamine-glutamate metabolism and fatty acid metabolism are key components of the metabolic phenotype in these mutants.

genetics↗

bioRxiv2023

Motor nerves direct the development of the sympathetic nervous system

The sympathetic nervous system controls a wide spectrum of bodily functions including operation of vessels, cardiac rhythm, and the "flight or fight response". Sympathetic neurons, which are neural crest-derived, develop in coordination with presynaptic motor nerves extending from the central nervous system (CNS). By using nerve-selective genetic ablations, we revealed that sympathetic ganglia development depends on CNS-derived motor innervation. In the absence of preganglionic motor nerves, trunk sympathetic chain ganglia were fragmented and smaller in size, while cervical ganglia were severely misshapen. Sympathetic neurons were misplaced along sensory fibers and projected towards abnormal paths, in some cases invading the sensory dorsal root ganglia. The misplaced progenitors of sympathoblasts corresponded to the nerve-associated, neural crest-derived Schwann cell precursors (SCPs). Notably, we found that SCPs activate the autonomic marker PHOX2B while migrating along motor nerves towards the region of the dorsal aorta in wildtype embryos, suggesting that SCP differentiate into sympathetic neurons while still nerve-associated in motor-ablated embryos. Ligand-receptor prediction from single cell transcriptomic data coupled with functional studies identified Semaphorin 3A/3F as candidate motor nerve-derived signals influencing neural crest migration along axons. Thus, motor nerves control the placement of sympathoblasts and their subsequent axonal navigation during critical periods of sympathetic chain development.

developmental biology↗

bioRxiv2022

RoboEM: automated 3D flight tracing for synaptic-resolution connectomics

Mapping neuronal networks from 3-dimensional electron microscopy data still poses substantial reconstruction challenges, in particular for thin axons. Currently available automated image segmentation methods, while substantially progressed, still require human proof reading for many types of connectomic analyses. RoboEM, an AI-based self-steering 3D flight system trained to navigate along neurites using only EM data as input, substantially improves automated state-of-the-art segmentations and replaces human proof reading for more complex connectomic analysis problems, yielding computational annotation cost for cortical connectomes about 400-fold lower than the cost of manual error correction.

neuroscience↗

bioRxiv2020

Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders.

Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unraveled Beclin-1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell penetrating autophagy inducing Tat-Beclin-1 (TB-1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB-1 reduced urinary orotic acid and hyperammonemia, and improved survival under protein-rich diet in spf-ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB-1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin-1-dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.

genetics↗

bioRxiv2018

Dense connectomic reconstruction in layer 4 of the somatosensory cortex

The dense circuit structure of the mammalian cerebral cortex is still unknown. With developments in 3-dimensional (3D) electron microscopy, the imaging of sizeable volumes of neuropil has become possible, but dense reconstruction of connectomes from such image data is the limiting step. Here, we report the dense reconstruction of a volume of about 500,000 m3 from layer 4 of mouse barrel cortex, about 300 times larger than previous dense reconstructions from the mammalian cerebral cortex. Using a novel reconstruction technique, FocusEM, we were able to reconstruct a total of 0.9 meters of dendrites and about 1.8 meters of axons investing only about 4,000 human work hours, about 10-25 times more efficient than previous dense circuit reconstructions. We find that connectomic data alone allows the definition of inhibitory axon types that show established principles of synaptic specificity for subcellular postsynaptic compartments. We find that also a fraction of excitatory axons exhibit such subcellular target specificity. Only about 35% of inhibitory and 55% of excitatory synaptic subcellular innervation can be predicted from the geometrical availability of membrane surface, revoking coarser models of random wiring for synaptic connections in cortical layer 4. We furthermore find evidence for enhanced variability of synaptic input composition between neurons at the level of primary dendrites in cortical layer 4. Finally, we obtain evidence for Hebbian synaptic weight adaptation in at least 24% of connections; at least 35% of connections show no sign of such previous plasticity. Together, these results establish an approach to connectomic phenotyping of local dense neuronal circuitry in the mammalian cortex.

neuroscience↗