Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury

Laug, Dylan; Huang, Teng-Wei; Huerta, Navish A. Bosquez; Huang, Anna Yu-Szu; Sardar, Debosmita; Ortiz-Guzman, Joshua; Carlson, Jeffrey; Arenkiel, Benjamin R.; Kuo, Chay T.; Mohila, Carrie A.; Glasgow, Stacey M.; Lee, Hyun Kyoung; Deneen, Benjamin

doi:10.1172/jci127492

Cited by 49 publications

(42 citation statements)

References 54 publications

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“…Likewise, while most up-regulated genes showed increased accessibility, such as Shh and Sox4 , some showed decreased accessibility. These divergent responses indicate that NFI genes control the expression of a large number of transcription factors in tanycytes, which appear to perform dual roles as both activators and repressors, as has previously been reported in other astroglial cell types ( 22 , 26 , 27 ).…”

Section: Resultssupporting

confidence: 62%

Control of neurogenic competence in mammalian hypothalamic tanycytes

et al. 2021

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Hypothalamic tanycytes, radial glial cells that share many features with neuronal progenitors, can generate small numbers of neurons in the postnatal hypothalamus, but the identity of these neurons and the molecular mechanisms that control tanycyte-derived neurogenesis are unknown. In this study, we show that tanycyte-specific disruption of the NFI family of transcription factors (Nfia/b/x) robustly stimulates tanycyte proliferation and tanycyte-derived neurogenesis. Single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis reveals that NFI (nuclear factor I) factors repress Sonic hedgehog (Shh) and Wnt signaling in tanycytes and modulation of these pathways blocks proliferation and tanycyte-derived neurogenesis in Nfia/b/x-deficient mice. Nfia/b/x-deficient tanycytes give rise to multiple mediobasal hypothalamic neuronal subtypes that can mature, fire action potentials, receive synaptic inputs, and selectively respond to changes in internal states. These findings identify molecular mechanisms that control tanycyte-derived neurogenesis, which can potentially be targeted to selectively remodel the hypothalamic neural circuitry that controls homeostatic physiological processes.

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Section: Resultssupporting

confidence: 62%

Control of neurogenic competence in mammalian hypothalamic tanycytes

et al. 2021

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“…First, astrocytes in healthy CNS exhibit multiple different molecular expression patterns that are associated with homeostatic functions [36]. Second, assigning the term 'homeostatic' only to astrocytes in healthy tissue implies that reactive astrocytes are by definition 'nonhomeostatic', which can be misleading because the disease-associated changes undergone by some reactive astrocytes can exert homeostatic activities that preserve BBB function [64], tissue integrity [32], and neurological functions [65]. Third, there is already substantial evidence that multiple molecular expression patterns are associated with reactive astrocytes in different disorder contexts rather than a single 'disease-associated' pattern [17,23,34,50,[55][56][57][58][59][60][61]63].…”

Section: Molecular Signatures and Nomenclaturementioning

confidence: 99%

Astrocyte Reactivity: Subtypes, States, and Functions in CNS Innate Immunity

Sofroniew

2020

Trends in Immunology

470

393

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Astrocytes are neural parenchymal cells that ubiquitously tile the central nervous system (CNS). In addition to playing essential roles in healthy tissue, astrocytes exhibit an evolutionarily ancient response to all CNS insults, referred to as astrocyte reactivity. Long regarded as passive and homogeneous, astrocyte reactivity is being revealed as a heterogeneous and functionally powerful component of mammalian CNS innate immunity. Nevertheless, concepts about what astrocyte reactivity comprises and what it does are incomplete and sometimes controversial. This review discusses the goal of differentiating reactive astrocyte subtypes and states based on composite pictures of molecular expression, cell morphology, cellular interactions, proliferative state, normal functions, and disease-induced dysfunctions. A working model and conceptual framework is presented for characterizing the diversity of astrocyte reactivity. Astrocyte Diversity in Health and DiseaseAstrocytes (see Glossary) are glial cells of neural progenitor origin that contiguously tile the entire mammalian central nervous system (CNS,) where they constitute one of the most abundant cell populations and provide multiple activities essential for CNS functions in health and disease [1]. Astrocytes interact with both neural and non-neural cells, including neurons and their synapses, oligodendrocytes, oligodendrocyte progenitor cells (OPCs), microglia, various perivascular cells, meningeal fibroblasts, and circulating immune cells. In healthy CNS tissue, astrocytes maintain homeostasis of extracellular fluids, ions, and transmitters [2], provide glucose metabolites as energy substrates to neurons [3], modulate local blood flow [4], help to regulate drainage of interstitial fluid [5], play essential roles in synapse development and plasticity [6], and exhibit dynamic activities that are crucial for neural circuit function, neurological function, and behavior [7].In addition to their functions in healthy CNS, astrocytes exhibit an evolutionarily ancient response to CNS injury and disease, commonly referred to as astrocyte reactivity, that was long regarded as homogeneous and functionally passive [1,[8][9][10]. Instead, over the past 25 years experimental studies using causation-testing transgenic manipulations and other technologies revealed that astrocyte reactivity can lead to a diverse set of potential changes in astrocyte morphology, molecular expression, and functions that can powerfully influence outcomes in all types of CNS disorders including traumatic injury [11][12][13], autoimmune inflammation [14][15][16][17][18], microbial infections [19][20][21], tumor formation [22,23], exposure to environmental toxins [24,25], peripheral metabolic disorders [26], and neurodegenerative diseases [27][28][29]. An extensive body of literature shows that reactive astrocytes can respond to diverse molecular signals that derive from many cell types including neurons, other glia, local stromal cells, microbes, and serum proteins, as well as blood-borne immune cells an...

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“…Moreover, a genetic variant with enhanced NF-κB activation in astrocytes is associated with MS [ 48 ]. Additional functional regulators of astrocyte reactivity are signal transducer activator of transcription 3 (STAT3) [ 49 , 50 ] and astrocytic nuclear factor 1A (NF1A) [ 51 ]. It is still unclear what molecular cues drive the expression of these transcription factors, how they interact, and if they underlie the formation of unique types of reactive astrocytes.…”

Section: Astrocyte Activation By Inflammatory Stimulationmentioning

confidence: 99%

Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions

Aharoni

Arnon

2021

IJMS

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In multiple sclerosis (MS), astrocytes respond to the inflammatory stimulation with an early robust process of morphological, transcriptional, biochemical, and functional remodeling. Recent studies utilizing novel technologies in samples from MS patients, and in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), exposed the detrimental and the beneficial, in part contradictory, functions of this heterogeneous cell population. In this review, we summarize the various roles of astrocytes in recruiting immune cells to lesion sites, engendering the inflammatory loop, and inflicting tissue damage. The roles of astrocytes in suppressing excessive inflammation and promoting neuroprotection and repair processes is also discussed. The pivotal roles played by astrocytes make them an attractive therapeutic target. Improved understanding of astrocyte function and diversity, and the mechanisms by which they are regulated may lead to the development of novel approaches to selectively block astrocytic detrimental responses and/or enhance their protective properties.

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Nuclear factor I-A regulates diverse reactive astrocyte responses after CNS injury

Cited by 49 publications

References 54 publications

Control of neurogenic competence in mammalian hypothalamic tanycytes

Control of neurogenic competence in mammalian hypothalamic tanycytes

Astrocyte Reactivity: Subtypes, States, and Functions in CNS Innate Immunity

Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions

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