Biology subjects

Liddelow, S. A.

Publications and source records attributed to Liddelow, S. A..

15 recordsLinked to original sources

bioRxiv2026

Ancient Somatosensory Circuit Architectures Employ Flexible Molecular Strategies

The extent to which conserved neural circuit architectures depend on shared molecular specification programs remains unclear. Here, we address this question by examining the somatosensory system of the little skate, Leucoraja erinacea, an early-diverging vertebrate that retains ancestral features of both finned and limb-based body plans. We show that core features of somatosensory circuit organization, including laminar organization of the spinal cord and dorsally restricted targeting of sensory afferents, are deeply conserved. Unexpectedly, the molecular programs specifying dorsal root ganglion (DRG) sensory subtypes diverge extensively from those of mammals. Although DRG neuron subtype specification and spinal connectivity rely on target-derived cues, skates employ distinct neurotrophin receptor and transcription factor identity codes. These findings support a model in which conserved spinal circuit architectures provide a stable scaffold that leverages flexible sensory neuron specification programs, enabling the evolutionary diversification of vertebrate somatosensory systems.

neuroscience↗

bioRxiv2026

IFNγ and proinflammatory cytokines cooperatively license astrocytes to support antigen-dependent CD4+ T cell restimulation

We report that type 2 interferon with proinflammatory cytokines induces astrocytes to express multiple components required for attraction of and antigen presentation to CD4+ T cells via MHC-II molecules. Re-analysis of astrocyte-enriched single-cell sequencing from bacterial mimetic-injected mice revealed a transcriptionally distinct interferon-responsive astrocyte population enriched for antigen-presentation-associated genes 24 hours after peripheral immune challenge. In vivo, we identify MHC-II+GFAP+ astrocytes localized to the surface of the brain across multiple mouse models of neuroinflammation and in human neurological disease tissue. In a pure in vitro culture system, astrocytes stimulated with IFN{gamma} and proinflammatory cytokines express MHC-II, costimulatory molecules and lymphocyte-recruiting chemokines, and support rapid antigen-dependent expansion of previously activated CD4+ T cells. Using human iPSC-derived CNS cultures, we additionally show induction of antigen-presentation-associated machinery in human astrocytes following inflammatory cytokine stimulation. Rather than inferring function solely from marker expression, we assessed astrocyte-supported T cell restimulation in vitro and separately characterized the emergence of antigen-presentation-associated astrocytes in vivo at neuroimmune interfaces during inflammation in mice and humans. Together, these findings support a conserved role for cytokine-stimulated astrocytes in expressing antigen-presentation-associated machinery and, in vitro, supporting antigen-dependent restimulation/expansion of CD4+ T cells under inflammatory conditions.

neuroscience↗

bioRxiv2026

Astrocytes mediate a positive feedback loop for oxytocin

Social interactions are critical for well-being and survival. Oxytocin neurons in the paraventricular nucleus of the hypothalamus help regulate social behaviors in many species, and respond to social stimuli to promote pro-social interactions. Here, we show that chronic social isolation reduced production of oxytocin peptide, and led to a delay in the onset of huddling behavior upon resocialization in male mice. Exogenous oxytocin treatment prevented both the behavioral and molecular effects of social deprivation. Using conditional knockouts, we found that oxytocin-induced oxytocin expression was mediated by local hypothalamic astrocytes. Oxytocin signaling in astrocytes upregulated the expression of a retinoic acid-synthesizing enzyme Aldh1a1, and retinoic acid increased oxytocin expression. These findings reveal a mechanism in which astrocytes can sense and control neuropeptide levels to influence social behaviors.

neuroscience↗

bioRxiv2025

Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here we demonstrate that microglia, resident macrophages of the brain, coordinate metabolic coupling between endothelial cells, astrocytes, and neurons to fuel protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, increasing glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit required for on-demand protein synthesis in mouse motor cortex.

neuroscience↗

bioRxiv2025

Genome writing to dissect consequences of SVA retrotransposon disease X-Linked Dystonia Parkinsonism

Human retrotransposon insertions are often associated with diseases. In the case of the neurodegenerative X-Linked Dystonia-Parkinsonism disease, a human-specific SINE-VNTR-Alu subfamily F retrotransposon was inserted in intron 32 of the TAF1 gene. Here, we genomically rewrote a portion of the mouse Taf1 allele with the corresponding 78-kb XDP patient derived TAF1 allele. In mESCs, the presence of the intronic SVAs--rather than the hybrid gene structure--reduces hyTAF1 levels. This leads to transcriptional downregulation of genes with TATA box enriched in their promoters and triggering apoptosis. Chromatin and transcriptome profiling revealed that intronic SVAs are actively transcribed, forming barriers that likely impede transcription elongation. In mice, neuronal lineage TAF1 humanization resulted lethality of male progeny within two months. XDP male mice had severe atrophy centered on the striatum--the same affected brain region in XDP patients. Lastly, CRISPRa-mediated activation of hyTAF1 restored mESC viability, suggesting boosting TAF1 transcription as a therapeutic approach.

genetics↗

bioRxiv2025

Myelin pathology is a key feature of X-linked Dystonia Parkinsonism

X-linked Dystonia-Parkinsonism (XDP) is a progressive, adult-onset neurodegenerative movement disorder that predominantly affects males of Filipino descent1-3. The disease is caused by the insertion of a SINE-VNTR-Alu subfamily F (SVA_F) retrotransposon within an intron of the TATA-box binding protein-associated factor 1 (TAF1) gene4. A major barrier to understanding the pathophysiology of XDP has been the lack of relevant animal models. Here, we introduce a novel conditional humanized XDP mouse model harboring a hybrid mouse-human Taf1/TAF1 gene (hyTAF1) containing the pathogenic SVA_F insertion. We activated the hyTAF1 in Nestin+ neural progenitor cells and found that the resulting XDP male mice recapitulate features of the human disease including severe motor impairment, striatal atrophy, and reactive gliosis. Transcriptomic, histological, and electron microscopy analysis revealed a dramatic reduction in oligodendrocyte lineage cells and widespread myelin disruption. Consistent with these findings, postmortem brain tissue from XDP patients revealed similar myelin pathology, including near-complete loss of myelin in parts of the medial prefrontal cortex. Together, these results identify oligodendrocyte dysfunction and myelin loss as previously unrecognized contributors to XDP pathogenesis, providing new mechanistic insight into this debilitating disorder.

neuroscience↗

bioRxiv2025

Astrocytes connect specific brain regions through plastic gap junctional networks

Traditionally, neuronal axons have been considered the primary mediators of functional connectivity among brain regions. However, the role of astrocyte-mediated communication has been largely underappreciated. While astrocytes communicate with one another through gap junctions, the extent and specificity of this communication remain poorly understood. Astrocyte gap junctions are necessary for memory formation1,2, synaptic plasticity3-5, coordination of neuronal signaling6, and closing the visual and motor critical periods7,8. These findings indicate that this form of communication is essential for proper central nervous system development and function. Despite their significance, studying astrocyte gap junctional networks has been challenging. Current methods like slice electrophysiology disrupt network connectivity and introduce artifacts due to tissue damage. To overcome these limitations, we developed a vector-based approach that labels molecules as they are fluxed by astrocyte gap junctions in awake, behaving animals. We then used whole-brain tissue clearing9,10 to image these intact, three-dimensional astrocyte networks. We show that multiple astrocyte networks traverse the mouse brain. These networks selectively connect specific regions, rather than diffusing indiscriminately, and vary in size and organization. We observe local networks are confined to single brain regions and long-range networks robustly interconnecting multiple regions across hemispheres, often exhibiting patterns distinct from known neuronal networks. Further, we demonstrate that astrocyte networks undergo structural reorganization in adult brain following sensory deprivation. These discoveries reveal a previously unrecognized mode of communication between distant brain regions, mediated by plastic networks of gap junction-coupled astrocytes.

neuroscience↗

bioRxiv2025

Epigenetic memory astrocytes are likely an artifact of immune cell contamination

Innate immune memory, in which prior immune stimuli can "train" certain immune cells to respond more aggressively to subsequent challenges, is crucial for immune system plasticity in disease. Lee et al. [1] recently described a similar kind of immune memory state in astrocytes which they termed "epigenetic memory astrocytes". The discovery of astrocytes with immune memory could have tremendous importance in understanding and treating neurological disease. However, the RNA-seq data and in vitro experiments presented by Lee et al. to claim astrocytes possess pro-inflammatory immune memory show signs of immune cell contamination. Further, astrocyte-specific knockout of Ep300, the purported epigenetic regulator of this memory, did not reduce expression of any memory astrocyte signature genes. The FIND-seq signature used to verify the presence of epigenetic memory astrocytes in experimental autoimmune encephalomyelitis (EAE) also shows signs of immune cell contamination, and the cells identified as memory astrocytes in previously published EAE single-cell RNA-seq data are misannotated macrophages. Lastly, we find the purported epigenetic memory astrocytes identified in single-nucleus RNA-seq data of multiple sclerosis (MS) tissue are an artifact of ambient RNA, low quality nuclei, and non-astrocyte contamination. We conclude that the epigenetic memory astrocyte signature is likely driven by immune cell contamination and the existence of astrocyte immunological memory is insufficiently evidenced. We caution that astrocyte transcriptomic, epigenomic, and functional assays must take care to exclude contamination by immune cells, especially when evaluating the potential of astrocytes to perform immunological functions.

neuroscience↗

bioRxiv2023

Defining the molecular identity and morphology of glia limitans superficialis astrocytes in mouse and human

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: Myocilin (Myoc). We show that Myoc+ astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from rodents to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.

neuroscience↗

bioRxiv2022

Determinants of Motor Neuron Functional Subtypes Important for Locomotor Speed

Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally-distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using single-cell RNA profiling in embryonic and larval zebrafish, we identify novel and conserved molecular signatures for MN functional subtypes, and identify genes expressed in both early post-mitotic and mature MNs. Assessing MN development in genetic mutants, we define a molecular program essential for MN functional subtype specification. Two evolutionarily-conserved transcription factors, Prdm16 and Mecom, are both functional subtype-specific determinants integral for fast MN development. Loss of prdm16 or mecom causes fast MNs to develop transcriptional profiles and innervation similar to slow MNs. These results reveal the molecular diversity of vertebrate axial MNs and demonstrate that functional subtypes are specified through intrinsic transcriptional codes.

neuroscience↗

bioRxiv2022

Silencing neuroinflammatory reactive astrocyte activating factors ameliorates disease outcomes in perinatal white matter injury

The role of reactive astrocytes in perinatal white matter injury (WMI) is unclear. In a mouse model of WMI, we provide evidence that impairing the formation of a C3-expressing neuroinflammatory reactive astrocyte sub-state rescues myelination and behavioral deficits. We further demonstrate the presence of C3-expressing reactive astrocytes in human WMI. Our data point to these cells as putative drivers of myelination failure in WMI and a potentially promising therapeutic target.

neuroscience↗

bioRxiv2022

INPP5D limits plaque formation and glial reactivity in the APP/PS1 mouse model of Alzheimer's disease

The dual specificity lipid/protein phosphatase SHIP1 (encoded by the INPP5D gene) is enriched in myeloid cells. Single nucleotide polymorphisms (SNPs) in INPP5D coding and non-coding regions impact risk for developing late onset sporadic Alzheimers disease (LOAD). We present pathological analyses with spatial transcriptomics of mice with tamoxifen-sensitive microglial knockdown of Inpp5d and show exacerbated plaque pathology, plaque-associated microglial density, and altered gene expression around plaques, suggesting novel markers for plaque-associated reactive microglia.

neuroscience↗

bioRxiv2021

Early stage differentiation of glia in human and mice.

Macroglia (astrocytes and oligodendrocytes) are required for normal development and function of the central nervous system, yet many questions remain about their emergence in the brain and spinal cord. Here we used single-cell RNA sequencing (scRNAseq) to analyze over 298,000 cells and nuclei during macroglia differentiation from mouse embryonic and human induced pluripotent stem cells. We computationally identify candidate genes involved in fate specification of glia in both species, and report heterogeneous expression of astrocyte surface markers across differentiating cells. We then used our scRNAseq data to optimize a previous mouse astrocyte differentiation protocol, decreasing the overall protocol length and complexity. Finally, we used multiomic, dual single nuclei (sn)RNAseq/snATACseq analysis to uncover potential genomic regulatory sites mediating glial differentiation. These datasets enable future optimization of glial differentiation protocols and provide insight into human glial differentiation.

neuroscience↗

bioRxiv2019

Melanoma-secreted Amyloid Beta Supresses Neuroinflammation and Promotes Brain Metastasis

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We performed unbiased proteomics analysis of melanoma short-term cultures, a novel model for the study of brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. This raised the exciting hypothesis that molecular pathways implicated in neurodegenerative disorders are critical for metastatic adaptation to the brain. Here, we show that melanoma cells require amyloid beta (A{beta}), a polypeptide heavily implicated in Alzheimers disease, for growth and survival in the brain parenchyma. Melanoma cells produce and secrete A{beta}, which activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that pharmacological inhibition of A{beta} decreases brain metastatic burden. Our results reveal a mechanistic connection between brain metastasis and Alzheimers disease - two previously unrelated pathologies, establish A{beta} as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma.

cancer biology↗

bioRxiv2018

Cell-autonomous regulation of astrocyte activation by the circadian clock protein BMAL1

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that the core clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism, and via a lesser non-cell-autonomous signal from neurons. Astrocyte-specific Bmal1 deletion induces astrocyte activation in vitro and in vivo, mediated in part by suppression of glutathione-s-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. Our results demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo, elucidating a novel mechanism by which the circadian clock could influence many aspects of brain function and neurologic disease.

neuroscience↗