Biology subjects

Carlson, E.

Publications and source records attributed to Carlson, E..

8 recordsLinked to original sources

bioRxiv2026

Neural birth time and somatosensory circuit assembly are linked by Robo3 regulation of dendrite morphology

Neural circuit wiring requires a remarkable level of precision, as thousands of neurons generate millions of synapses in distinct configurations. While neural circuits are known to be shaped by both neural birth timing and multiple classes of guidance molecules, the relationship between the two and how they coordinate circuit assembly has yet to be evaluated. Leveraging the well-defined stem cell lineages of the Drosophila embryonic nerve cord, we investigate how Roundabout (Robo) guidance receptors are regulated by neural birth timing to establish neural morphology and function for circuit assembly. Our data reveal that Robo receptor expression in neurons is tightly linked to neural birth timing and controlled by temporal transcription factors. Notably, we identify a Robo3 guidance receptor code that is pivotal for assembly of somatosensory circuits, distinguishing stretch-detecting PNS neurons and late-born EL interneurons (lacking Robo3) from vibration detecting PNS neurons and early-born EL interneurons (expressing Robo3). These insights propose a shared guidance receptor code connecting neural birth timing to circuit assembly, providing a molecular foundation for developmental wiring specificity. HighlightsO_LIRobo3 is enriched in early-born neurons and requires Pdm and Castor for normal expression C_LIO_LIClassic temporal identity markers and Robo3 are differentially regulated C_LIO_LIIn interneurons, Robo3 is required for dendrite positioning and branching C_LIO_LIA shared Robo code is used by synaptic partners from different developmental origins C_LI

developmental biology↗

bioRxiv2025

Alpha-synuclein aggregation and dopaminergic neuron death in a new mouse model of Parkinson disease expressing human full-length and C-terminally truncated 1-120 alpha-synuclein.

Parkinsons disease (PD) is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites made of aggregated alpha-synuclein (aSyn). Several studies have shown that Lewy bodies contain C-terminally truncated aSyn which is more prone to fibrillation and enhances the aggregation of human full-length aSyn in vitro. Nevertheless, in vivo studies addressing whether and how human C-terminally truncated aSyn may exacerbate the pathological aggregation and toxicity of human full-length aSyn are currently lacking. In the present study we aimed to determine whether the co-expression of human full-length and 1-120 truncated aSyn would enhance human full-length aSyn aggregation and toxicity. To this end we generated and characterized two novel alpha- synuclein mouse models. Specifically, we first produced a mouse line expressing full-length human aSyn under its own promoter (BACo mice) in the absence of endogenous mouse aSyn. Then, the BACo mice were crossed with the previously described MI2 mice, which express human 1-120 truncated aSyn under the control of the tyrosine hydroxylase (TH) promoter on a mouse aSyn null backgroundin order to obtain the MI2BACo mice, which express both human 1-120 truncated and full-length aSyn in a mouse aSyn null background. We found that aSyn aggregation was present and increased with age in both mouse lines but was significantly higher in the MI2BACo mice. These mice exhibited progressive nigrostriatal accumulation of aSyn aggregates which were often composed of full-length and 1-120haSyn, the latter being specifically recognized by using a novel antibody raised against the 1-120haSyn. In addition, we observed that the presence of both truncated and full-length aSyn in MI2BACo mice led to a faster and more pronounced aSyn aggregation which associated with more severe dopaminergic striatal fiber degeneration and nigral neuron loss. Collectively, our results indicate that the expression of human C-terminally truncated aSyn exacerbates human full-length aSyn pathology and support that the novel MI2BACo transgenic mouse line represents an innovative experimental model to study the biological basis of PD and test novel therapeutic approaches.

neuroscience↗

bioRxiv2025

Improving American chestnut resistance to two invasive pathogens through genome-enabled breeding

Over a century after two introduced pathogens decimated American chestnut populations, breeding programs continue to incorporate resistance from Chinese chestnut to recover self-sustaining populations. Due to complex genetics of chestnut blight resistance, it is challenging to obtain trees with sufficient resistance and competitive growth. We developed high quality reference genomes for Chinese and American chestnut and leveraged large disease phenotype and genotype datasets to develop accurate genomic selection. Inoculation and simulation results indicate that resistance may be substantially increased in trees that inherited 70% to 100% of their genome from American chestnut. To facilitate gene editing, we integrated multiple lines of evidence to discover candidate alleles for blight resistance and susceptibility. These genomic resources provide a strong foundation to accelerate restoration of this iconic tree.

genomics↗

bioRxiv2024

Etiology of Craniofacial and Cardiac Malformations in a Mouse Model of SF3B4-Related Syndromes

Pathogenic variants in SF3B4 are responsible for the acrofacial disorders Nager and Rodriguez Syndrome, also known as SF3B4-related Syndromes, associated with malformations in the head, face, limbs, vertebrae as well as the heart. To uncover the etiology of craniofacial malformations found in SF3B4-related syndromes, mutant mouse lines with homozygous deletion of Sf3b4 in neural crest cells (NCC) were generated. Like in human patients, these embryos had craniofacial and cardiac malformations with variable expressivity and penetrance. The severity and survival of Sf3b4 NCC mutants was modified by the level of Sf3b4 in neighbouring non NCC. RNA sequencing analysis of heads of embryos prior to morphological abnormalities showed significant changes in expression of genes forming the NCC regulatory network, as well as an increase in exon skipping. We identified several key transcription factors and histone modifiers involved in craniofacial and cardiac development with increased exon skipping. Increased exon skipping was also associated with use of a more proximal branch point, as well as an enrichment in thymidine bases in the 50bp around the branch points. We propose that decrease in Sf3b4 causes changes in the expression and splicing of transcripts required for proper craniofacial and cardiac development, leading to abnormalities.

developmental biology↗

bioRxiv2023

Multiplicity of Agrobacterium infection of Nicotiana benthamiana for transient DNA delivery

Biological DNA transfer into plant cells mediated by Agrobacterium represents one of the most powerful tools for the engineering and study of plant systems. Transient expression of transfer DNA (T-DNA) in particular enables rapid testing of gene products and has recently been harnessed for facile combinatorial expression of multiple genes. In analogous mammalian cell-based gene expression systems, a clear sense of the multiplicity of infection (MOI) allows users to predict and control viral transfection frequencies for applications requiring single vs. multiple transfection events per cell. Despite the value of Agrobacterium-mediated transient transformation of plants, MOI has not been quantified. Establishing MOI for Agrobacterium T-DNA delivery at the level of single plant cells would allow users to design genomic library delivery conditions (at most 1 event/cell), or maximize co-delivery of T-DNA loads from separate Agrobacterium (>1 event/cell). Here, we analyze the Poisson probability distribution of T-DNA transfer in leaf pavement cells to determine the MOI for the widely used model system Agrobacterium GV3101/Nicotiana benthamiana. These data delineate the relationship between an individual Agrobacterium strain infiltration OD600, plant cell perimeter and leaf age, as well as plant cell co-infection rates. Our analysis also establishes experimental regimes where the probability of near-simultaneous delivery of >20 unique T-DNAs to a given plant cell remains high throughout the leaf. We anticipate that these data will enable users to develop new approaches to in-leaf library development using Agrobacterium transient expression and the reliable combinatorial assaying of multiple heterologous proteins in a single plant cell.

plant biology↗

bioRxiv2021

Trait empathy modulates music-related functional connectivity.

It has been well established through behavioural studies that empathy significantly influences music perception. Such individual differences typically manifest as variability in whole brain functional connectivity patterns. To date, nobody has examined the modulatory effect of empathy on functional connectivity patterns during continuous music listening. In the present study, we seek to investigate the global and local connectivity patterns of 36 participants whose fMRI scanning was done by employing the naturalistic paradigm wherein they listened to a continuous piece of music. We used graph-based measures of functional connectivity to identify how cognitive and affective components of empathy modulate functional connectivity. Partial correlation between Eigenvector centrality and measures of empathy showed that cognitive empathy is associated with higher centrality in the sensorimotor regions responsible for motor mimicry while affective empathy showed higher centrality in regions related to auditory affect processing. We furthermore identified a left-hemispheric dominance in the modulatory effect of affective empathy particularly in the Orbitofrontal cortex and the temporal pole. Results are discussed in relation to various theoretical models of empathy and music cognition.

neuroscience↗

bioRxiv2021

Varenicline Prevents SARS-CoV-2 Infection In Vitro and in Rhesus Macaques

BackgroundSARS-CoV-2 infections have resulted in a global pandemic, but an antiviral therapy for this novel strain of coronavirus does not currently exist. The objective of our study was to investigate the antiviral potential of the nicotinic acetylcholine receptor (nACHR) agonist varenicline tartrate against SARS-CoV-2. MethodsWe assessed antiviral activity using in vitro human cell assays and we assessed in vivo efficacy in a rhesus macaque model. ResultsIn vitro studies found that varenicline tartrate, over a range of concentrations, reduced the infectivity of SARS-CoV-2 wildtype, alpha, and beta variants in Calu-3 cells and Caco-2 cells, with maintenance of cell viability. In vivo studies found that varenicline tartrate, administered as a nasal spray to rhesus macaques, reduced SARS-CoV-2 wildtype viral load and inhibited viral replication in the nasal mucosa and upper airway. ConclusionAlthough the study reported here was exploratory, we have confirmed that the nAChR agonist varenicline has the potential to interact with and inhibit SARS-CoV-2 infection and replication.

immunology↗

bioRxiv2020

CSPα reduces aggregates and rescues striatal dopamine release in αsynuclein transgenic mice

Synuclein aggregation at the synapse is an early event in Parkinsons disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSP) and synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSP is a member of the DNAJ/HSP40 family of co-chaperones and like synuclein, chaperones the SNARE complex assembly and neurotransmitter release. Synuclein can rescue neurodegeneration in CSPKO mice. However, whether synuclein aggregation alters CSP expression and function is unknown. Here we show that synuclein aggregation at the synapse induces a decrease in synaptic CSP and a reduction in the complexes that CSP forms with HSC70 and STGa. We further show that viral delivery of CSP rescues in vitro the impaired vesicle recycling in PC12 cells with synuclein aggregates and in vivo reduces synaptic synuclein aggregates restoring normal dopamine release in 1-120hsyn mice. These novel findings reveal a mechanism by which synuclein aggregation alters CSP at the synapse, and show that CSP rescues synuclein aggregation-related phenotype in 1-120hsyn mice similar to the effect of synuclein in CSPKO mice. These results implicate CSP as a potential therapeutic target for the treatment of early-stage PD.

neuroscience↗