Biology subjects

Nagel, M.

Publications and source records attributed to Nagel, M..

17 recordsLinked to original sources

bioRxiv2026

Deep-tissue mechanosensation emerges from the interaction of external force and internal tissue state

Muscle sensation is often considered in terms of proprioception, but muscle pain illustrates that other types of sensory neurons are also involved. Here, we show that trigeminal neurons innervating the masseter muscle fall into three classes: A{beta} low-threshold mechanoreceptors, A{delta} high-threshold mechanoreceptors (A{delta}-HTMRs), and peptidergic neurons (PEP). All three types are recruited by mechanical stimulation, with massage being a particularly effective stimulus. Chemogenetic activation of masseter A{delta}-HTMRs and PEP neurons results in pain-like symptoms. Moreover, acute and chronic inflammation sensitize nociceptors, altering behavioral tolerance in an animal model of massage. Taken together, our results provide a framework for understanding muscle somatosensation and how massage of sore muscles may be painful yet beneficial. SignificanceMuscle sensation is usually most prominent when something goes wrong: after overuse, injury, or inflammation, even ordinary pressure or movement can become painful. Yet how mechanical force is detected in muscle, and when a stimulus becomes painful, remain poorly understood. Here, we identify a simple cellular organization for muscle mechanosensation in which three sensory-neuron classes encode force through graded population recruitment. Massage effectively recruited all three classes, including the two nociceptive populations. We further show that these nociceptive neurons are sensitized by acute and chronic inflammation, leading to enhanced recruitment during massage. These findings show that the representation of mechanical force in muscle can be shaped by tissue state and provide a foundation for understanding muscle soreness, pain, and therapeutic touch.

neuroscience↗

bioRxiv2025

Multi-omics and biochemical reconstitution reveal CDK7-dependent mechanisms controlling RNA polymerase II function at gene 5'- and 3'-ends

CDK7 regulates RNA polymerase II (RNAPII) initiation, elongation, and termination through incompletely understood mechanisms. Because contaminating kinases precluded CDK7 analysis with nuclear extracts, we completed biochemical assays with purified factors. Reconstitution of RNAPII transcription initiation showed CDK7 inhibition slowed and/or paused RNAPII promoter-proximal transcription, which reduced re-initiation. These CDK7-regulatory functions were Mediator- and TFIID-dependent. Similarly in human cells, CDK7 inhibition reduced transcription by suppressing RNAPII activity at promoters, consistent with reduced initiation and/or re-initiation. Moreover, widespread 3-end readthrough transcription was observed in CDK7-inhibited cells; mechanistically, this occurred through rapid nuclear depletion of RNAPII elongation and termination factors, including high-confidence CDK7 targets. Collectively, these results define how CDK7 governs RNAPII function at gene 5-ends and 3-ends, and reveal that nuclear abundance of elongation and termination factors is kinase-dependent. Because 3-readthrough transcription is commonly induced during stress, our results further suggest regulated suppression of CDK7 activity may enable this RNAPII transcriptional response.

biochemistry↗

bioRxiv2024

Long-Read RNA-sequencing reveals transcript-specific regulation in human-derived cortical neurons

Long-read RNA sequencing has transformed transcriptome analysis by enabling comprehensive mapping of full-length transcripts, providing an unprecedented resolution of transcript diversity, alternative splicing, and transcript-specific regulation. In this study, we employed nanopore long-read RNA sequencing to profile the transcriptomes of human fibroblasts, induced pluripotent stem cells, and stem cell-derived cortical neurons, identifying extensive transcript diversity with 15,072 transcripts in stem cell-derived cortical neurons, 13,048 in fibroblasts, and 12,759 in induced pluripotent stem cells. Our analyses uncovered 35,519 differential transcript expression events and 5,135 differential transcript usage events, underscoring the complexity of transcriptomic regulation across these cell types. Importantly, by integrating differential transcript expression and usage analyses, we gained deeper insights into transcript dynamics that are not captured by gene-level expression analysis alone. Notably, differential transcript usage analysis highlighted transcript-specific changes in disease-relevant genes such as APP, KIF2A, and BSCL2, associated with Alzheimers disease, neuronal migration disorders, and degenerative axonopathies, respectively. This added resolution emphasizes the significance of transcript- level variations that often remain hidden in traditional differential gene expression analyses. Overall, our work provides a framework for understanding transcript diversity in both pluripotent and specialized cell types, which can be used to investigate transcriptomic changes in disease states. Additionally, this study underscores the utility of differential transcript usage analysis in advancing our understanding of neurodevelopmental and neurodegenerative diseases, paving the way for identifying transcript-specific therapeutic targets.

neuroscience↗

bioRxiv2024

Intradental mechano-nociceptors serve as sentinels that prevent tooth damage

Pain is the anticipated output of the trigeminal sensory neurons that innervate the tooths vital interior1,2; however, the contribution of intradental neurons to healthy tooth sensation has yet to be defined. Here, we employ in vivo Ca2+ imaging to identify and define a population of myelinated high-threshold mechano-nociceptors (intradental HTMRs) that detect superficial structural damage of the tooth, produce pain, and initiate a jaw opening reflex. Intradental HTMRs remain inactive when direct forces are applied to the intact tooth but become responsive to forces when the structural integrity of the tooth is compromised, and the dentin or pulp is exposed. Their terminals collectively innervate the inner dentin through overlapping receptive fields, allowing them to monitor the superficial structures of the tooth. Indeed, intradental HTMRs detect superficial enamel damage and encode its degree, and their responses persist in the absence of either PIEZO2 or Nav1.83,4. As predicted, chemogenetic activation of intradental HTMRs results in a marked pain phenotype like that produced by systemic chemogenetic activation of nociceptors. Remarkably, optogenetic activation of intradental HTMRs triggers a rapid, jaw opening reflex via contraction of the digastric muscle. Taken together, our data indicate that intradental HTMRs serve as sentinels that guard against mechanical threats to the tooth; their activation not only triggers pain, but also results in physical tooth separation, which would prevent damage during mastication. Our work provides a new perspective of intradental neurons, highlighting their protective role, and illustrates the functional diversity of interoreceptors.

neuroscience↗

bioRxiv2024

Unraveling Axonal Transcriptional Landscapes: Insights from iPSC-Derived Cortical Neurons and Implications for Motor Neuron Degeneration

Neuronal function and pathology are deeply influenced by the distinct molecular profiles of the axon and soma. Traditional studies have often overlooked these differences due to the technical challenges of compartment specific analysis. In this study, we employ a robust RNA-sequencing (RNA-seq) approach, using microfluidic devices, to generate high-quality axonal transcriptomes from iPSC-derived cortical neurons (CNs). We achieve high specificity of axonal fractions, ensuring sample purity without contamination. Comparative analysis revealed a unique and specific transcriptional landscape in axonal compartments, characterized by diverse transcript types, including protein-coding mRNAs, RNAs encoding ribosomal proteins (RPs), mitochondrial-encoded RNAs, and long non-coding RNAs (lncRNAs). Previous works have reported the existence of transcription factors (TFs) in the axon. Here, we detect a set of TFs specific to the axon and indicative of their active participation in transcriptional regulation. To investigate transcripts and pathways essential for central motor neuron (MN) degeneration and maintenance we analyzed KIF1C-knockout (KO) CNs, modeling hereditary spastic paraplegia (HSP), a disorder associated with prominent length-dependent degeneration of central MN axons. We found that several key factors crucial for survival and health were absent in KIF1C-KO axons, highlighting a possible role of these also in other neurodegenerative diseases. Taken together, this study underscores the utility of microfluidic devices in studying compartment-specific transcriptomics in human neuronal models and reveals complex molecular dynamics of axonal biology. The impact of KIF1C on the axonal transcriptome not only deepens our understanding of MN diseases but also presents a promising avenue for exploration of compartment specific disease mechanisms.

neuroscience↗

bioRxiv2023

Trigeminal innervation and tactile responses in mouse tongue

The mammalian tongue is richly innervated with somatosensory, gustatory and motor fibers. These form the basis of many ethologically important functions such as eating, speaking and social grooming. Despite its high tactile acuity and sensitivity, the neural basis of tongue mechanosensation remains largely mysterious. Here we explored the organization of mechanosensory afferents in the tongue and found that each lingual papilla is innervated by Piezo2+ trigeminal neurons. Notably, each fungiform papilla contained highly specialized ring-like sensory neuron terminations that asymmetrically circumscribe the taste buds. Myelinated lingual afferents in the mouse lingual papillae did not form corpuscular sensory end organs but rather had only free nerve endings. In vivo single-unit recordings from the trigeminal ganglion revealed lingual low-threshold mechanoreceptors (LTMRs) with conduction velocities in the A{delta} range or above and distinct adaptation properties ranging from intermediately adapting (IA) to rapidly adapting (RA). IA units were sensitive to both static indentation and stroking, while RA units had a preference for tangential forces applied by stroking. Lingual LTMRs were not directly responsive to rapid cooling or chemicals that can induce astringent or numbing sensations. Sparse labeling of lingual afferents in the tongue revealed distinct terminal morphologies and innervation patterns in fungiform and filiform papillae. Together, our results indicate that fungiform papillae are mechanosensory structures, while suggesting a simple model that links the functional and anatomical properties of tactile sensory neurons in the tongue.

neuroscience↗

bioRxiv2023

The rules of sex and strain: deciphering the chemical language of inbred and wild mouse conspecific scents

In most mammals, conspecific chemosensory communication relies on semiochemical release within complex bodily secretions and subsequent stimulus detection by the vomeronasal organ (VNO). Urine, a rich source of ethologically relevant chemosignals, conveys detailed information about sex, social hierarchy, health and reproductive state, which becomes accessible to a conspecific via vomeronasal sampling. So far, however, numerous aspects of social chemosignaling along the vomeronasal pathway remain unclear. Moreover, since virtually all research on vomeronasal physiology is based on secretions derived from inbred laboratory mice, it remains uncertain whether such stimuli provide a true representation of potentially more relevant cues found in the wild. Here, we combine a robust low-noise VNO activity assay with comparative molecular profiling of sex- and strain-specific mouse urine samples from two inbred laboratory strains as well as from wild mice. With comprehensive molecular portraits of these secretions, VNO activity analysis now enables us to (i) assess whether and, if so, how much sex- / strain-selective "raw" chemical information in urine is accessible via vomeronasal sampling; (ii) identify which chemicals exhibit sufficient discriminatory power to signal an animals sex, strain, or both; (iii) determine the extent to which wild mouse secretions are unique; and (iv) analyze whether vomeronasal response profiles differ between strains. We report both sex- and, in particular, strain-selective VNO representations of chemical information. Within the urinary secretome, both volatile compounds and proteins exhibit sufficient discriminative power to provide sex- and strain-specific molecular fingerprints. While total protein amount is substantially enriched in male urine, females secrete a larger variety at overall comparatively low concentrations. Surprisingly, the molecular spectrum of wild mouse urine does not dramatically exceed that of inbred strains. Finally, vomeronasal response profiles differ between C57BL/6 and BALB/c animals, with particularly disparate representations of female semiochemicals.

neuroscience↗

bioRxiv2022

Abundant pleiotropy across neuroimaging modalities identified through a multivariate genome-wide association study

Genetic pleiotropy is abundant across spatially distributed brain characteristics derived from one neuroimaging modality (e.g. structural, functional or diffusion MRI). A better understanding of pleiotropy across modalities could inform us on the integration of brain function, micro- and macrostructure. Here we show extensive genetic overlap across neuroimaging modalities at a locus and gene level in the UK Biobank (N=34,029) and ABCD Study (N=8,607). When jointly analysing phenotypes derived from structural, functional and diffusion MRI with the Multivariate Omnibus Statistical Test (MOSTest), we boost the discovery of loci and genes beyond previously identified effects for each modality individually. Cross-modality genes are involved in fundamental biological processes and predominantly expressed during prenatal brain development. We additionally boost prediction of psychiatric disorders by conditioning independent GWAS on our multimodal multivariate GWAS. These findings shed light on the shared genetic mechanisms underlying variation in brain morphology, functional connectivity, and tissue composition. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=192 SRC="FIGDIR/small/521181v3_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1e7eadcorg.highwire.dtl.DTLVardef@ec127eorg.highwire.dtl.DTLVardef@b21f14org.highwire.dtl.DTLVardef@1690c5_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2022

Reevaluation of Piezo1 as a gut RNA sensor

Piezo1 is a stretch-gated ion channel required for mechanosensation in many organ systems. Recent provocative findings describe a new role for Piezo1 in the gut, suggesting that it is a sensor of microbial single-stranded RNA (ssRNA) rather than mechanical force. If true, this would redefine the scope of Piezo biology. Here, we sought to replicate the central finding that fecal ssRNA is a natural agonist of Piezo1. While we observed that fecal extracts and ssRNA stimulate calcium influx in certain cell lines, this response was independent of Piezo1. Additionally, sterilized dietary extracts devoid of gut biome RNA showed similar cell line-specific stimulatory activity to fecal extracts. Together, our data highlight potential confounds inherent to gut-derived extracts, exclude Piezo1 as a receptor for ssRNA in the gut, and support a dedicated role for Piezo channels in mechanosensing.

cell biology↗

bioRxiv2022

The kinesin motor KIF1C is a putative transporter of the exon junction complex in neuronal cells

Neurons critically depend on regulated RNA localization and tight control of spatio-temporal gene expression to maintain their morphological and functional integrity. Mutations in the kinesin motor protein gene KIF1C cause Hereditary Spastic Paraplegia, an autosomal recessive disease leading to predominant degeneration of the long axons of central motoneurons. In this study we aimed to gain insight into the molecular function of KIF1C and understand how KIF1C dysfunction contributes to motoneuron degeneration. We used affinity proteomics in neuronally differentiated neuroblastoma cells (SH-SY5Y) to identify the protein complex associated with KIF1C in neuronal cells; candidate interactions were then validated by immunoprecipitation and mislocalization of putative KIF1C cargoes was studied by immunostainings. We found KIF1C to interact with all core components of the exon junction complex (EJC); expression of mutant KIF1C in neuronal cells leads to loss of the typical localization distally in neurites. Instead, EJC core components accumulate in the pericentrosomal region, here co-localizing with mutant KIF1C. These findings suggest KIF1C as a neuronal transporter of the EJC. Interestingly, the binding of KIF1C to the EJC is RNA-mediated, as treatment with RNAse prior to immunoprecipitation almost completely abolishes the interaction. Silica-based solid-phase extraction of UV-crosslinked RNA-protein complexes furthermore supports direct interaction of KIF1C with RNA, as recently also demonstrated for kinesin heavy chain. Taken together, our findings are consistent with a model where KIF1C transports mRNA in an EJC-bound and therefore transcriptionally silenced state along neurites, thus providing the missing link between the EJC and mRNA localization in neurons.

neuroscience↗

bioRxiv2022

Specificity and overlap in the genetic architectures of functional and structural connectivity within cerebral resting-state networks

The functional connectivity and dynamics of resting-state networks (RSN-FC) are vital for cognitive functioning. RSN-FC is heritable and partially translates to the anatomical architecture of white matter, but the genetic component of structural connections of RSNs (RSN-SC) and their potential genetic overlap with RSN-FC remains unknown. Here we perform genome-wide association studies (Ndiscovery=24,336; Nreplication=3,412) and in silico annotation on RSN-SC and RSN-FC. We identify the first genes for visual network-SC, that are involved in axon guidance and synaptic functioning and show that genetic variation in RSN-FC impacts biological processes related to brain disorders that have previously been associated with FC alterations in those same RSNs. Correlations of the genetic components of RSNs are mostly observed within the functional domain, whereas less overlap is observed within the structural domain and between the functional and structural domains. This study advances the understanding of the complex functional organization of the brain and its structural underpinnings from a genetics viewpoint.

genetics↗

bioRxiv2021

Genome-wide association study of cerebellar volume

Cerebellar volume is highly heritable and associated with neurodevelopmental and neurodegenerative disorders. Understanding the genetic architecture of cerebellar volume may improve our insight into these disorders. This study aims to investigate the convergence of cerebellar volume genetic associations in close detail. A genome-wide associations study for cerebellar volume was performed in a sample of 27,486 individuals from UK Biobank, resulting in 29 genome-wide significant loci and a SNP heritability of 39.82%. We pinpoint variants that have effects on amino acid sequence or cerebellar gene-expression. Additionally, 85 genome-wide significant genes were detected and tested for convergence onto biological pathways, cerebellar cell types or developmental stages. Local genetic correlations between cerebellar volume and neurodevelopmental and neurodegenerative disorders reveal shared loci with Parkinsons disease, Alzheimers disease and schizophrenia. These results provide insights into the heritable mechanisms that contribute to developing a brain structure important for cognitive functioning and mental health.

genetics↗

bioRxiv2021

Functional cooperativity mediated by rationally selected combinations of human monoclonal antibodies targeting the henipavirus receptor binding protein

Hendra virus (HeV) and Nipah virus (NiV), the prototypic members of the Henipavirus (HNV) genus, are emerging, zoonotic paramyxoviruses known to cause severe disease across six mammalian orders, including humans (Eaton et al., 2006). While several research groups have made strides in developing candidate vaccines and therapeutics against henipaviruses, such countermeasures have not been licensed for human use, and significant gaps in knowledge about the human immune response to these viruses exist. To address these gaps, we isolated a large panel of human monoclonal antibodies (mAbs) from the B cells of an individual with prior occupation-related exposure to the equine HeV vaccine (Equivac(R) HeV). Competition-binding and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies identified at least six distinct antigenic sites on the HeV/NiV receptor binding protein (RBP) that are recognized by human mAbs. Antibodies recognizing multiple antigenic sites potently neutralized NiV and/or HeV isolates in vitro. The most potent class of cross-reactive antibodies achieved neutralization by blocking viral attachment to the host cell receptors ephrin-B2 and ephrin-B3. Antibodies from this class mimic receptor binding by inducing a receptor-bound conformation to the HeV-RBP protein tetramer, exposing an epitope that appears to lie hidden in the interface between protomers within the HeV-RBP tetramer. Antibodies that recognize this cryptic epitope potently neutralized HeV and NiV. Flow cytometric studies using cell-surface-displayed HeV-RBP protein showed that cross-reactive, neutralizing mAbs from each of these classes cooperate for binding. In a highly stringent hamster model of NiVB infection, antibodies from both classes reduced morbidity and mortality and achieved synergistic protection in combination and provided therapeutic benefit when combined into two bispecific platforms. These studies identified multiple candidate mAbs that might be suitable for use in a cocktail therapeutic approach to achieve synergistic antiviral potency and reduce the risk of virus escape during treatment.

immunology↗

bioRxiv2019

GWAS of brain volume on 54,407 individuals and cross-trait analysis with intelligence identifies shared genomic loci and genes

The phenotypic correlation between human intelligence and brain volume (BV) is considerable (r{approx}0.40), and has been shown to be due to shared genetic factors1. To further examine specific genetic factors driving this correlation, we present genomic analyses of the genetic overlap between intelligence and BV using genome-wide association study (GWAS) results. First, we conducted the largest BV GWAS meta-analysis to date (N=54,407 individuals), followed by functional annotation and gene-mapping. We identified 35 genomic loci (27 novel), implicating 362 genes (346 novel) and 23 biological pathways for BV. Second, we used an existing GWAS for intelligence (N=269,867 individuals2), and estimated the genetic correlation (rg) between BV and intelligence to be 0.23. We show that the rg is driven by physical overlap of GWAS hits in 5 genomic loci. We identified 67 shared genes between BV and intelligence, which are mainly involved in important signaling pathways regulating cell growth. Out of these 67 we prioritized 32 that are most likely to have functional impact. These results provide new information on the genetics of BV and provide biological insight into BVs shared genetic etiology with intelligence.

genetics↗

bioRxiv2018

Genome-wide Analysis of Insomnia (N=1,331,010) Identifies Novel Loci and Functional Pathways

Insomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (N=1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia complaints. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.

genetics↗

bioRxiv2017

GWAS meta-analysis (N=279,930) identifies new genes and functional links to intelligence

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to intelligence3-7, but much about its genetic underpinnings remains to be discovered. Here, we present the largest genetic association study of intelligence to date (N=279,930), identifying 206 genomic loci (191 novel) and implicating 1,041 genes (963 novel) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and identify 89 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain and specifically in striatal medium spiny neurons and cortical and hippocampal pyramidal neurons. Gene-set analyses implicate pathways related to neurogenesis, neuron differentiation and synaptic structure. We confirm previous strong genetic correlations with several neuropsychiatric disorders, and Mendelian Randomization results suggest protective effects of intelligence for Alzheimers dementia and ADHD, and bidirectional causation with strong pleiotropy for schizophrenia. These results are a major step forward in understanding the neurobiology of intelligence as well as genetically associated neuropsychiatric traits.

genetics↗

bioRxiv2017

GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways

Neuroticism is an important risk factor for psychiatric traits including depression1, anxiety2,3, and schizophrenia4-6. Previous genome-wide association studies7-12 (GWAS) reported 16 genomic loci10-12. Here we report the largest neuroticism GWAS meta-analysis to date (N=449,484), and identify 136 independent genome-wide significant loci (124 novel), implicating 599 genes. Extensive functional follow-up analyses show enrichment in several brain regions and involvement of specific cell-types, including dopaminergic neuroblasts (P=3x10-8), medium spiny neurons (P=4x10-8) and serotonergic neurons (P=1x10-7). Gene-set analyses implicate three specific pathways: neurogenesis (P=4.4x10-9), behavioural response to cocaine processes (P=1.84x10-7), and axon part (P=5.26x10-8). We show that neuroticisms genetic signal partly originates in two genetically distinguishable subclusters13 (depressed affect and worry, the former being genetically strongly related to depression, rg=0.84), suggesting distinct causal mechanisms for subtypes of individuals. These results vastly enhance our neurobiological understanding of neuroticism, and provide specific leads for functional follow-up experiments.

genetics↗