Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration

eLife, Journal Year: 2023, Volume and Issue: 12

Published: May 26, 2023

Following acute injury, the capillary vascular bed in lung must be repaired to reestablish gas exchange with external environment. Little is known about transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation subsequent regeneration of capillaries, as well their response stress. Here, we show transcription factor Atf3 essential for regenerative mouse endothelium after influenza infection. expression defines a subpopulation ECs enriched genes involved development, differentiation, migration. During alveolar regeneration, this EC population expands increases angiogenesis, blood vessel cellular Importantly, cell-specific loss results defective part through increased apoptosis decreased endothelium. This leads general persistent morphological changes niche, including an emphysema-like phenotype enlarged airspaces lined regions lack investment. Taken together, these data implicate component injury required successful regeneration.

Language: Английский

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Injury distance limits the transcriptional response to spinal injury

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 1, 2024

Abstract The ability of neurons to sense and respond damage is fundamental homeostasis nervous system repair. For some cell types, notably dorsal root ganglia (DRG) retinal ganglion cells (RGCs), extensive profiling has revealed a large transcriptional response axon injury that determines survival regenerative outcomes. In contrast, the most supraspinal whose limited regeneration constrains recovery from spinal injury, mostly unknown. Here we employed single-nuclei sequencing in mice profile responses diverse types injury. Surprisingly, thoracic triggered only modest changes gene expression across all populations, including corticospinal tract (CST) neurons. Moreover, CST also responded minimally cervical but much more strongly intracortical axotomy, upregulation numerous apoptosis-related transcripts shared with injured DRG RGC Thus, muted neuron linked injury’s distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate central challenge for enhancing after sensing distant injuries subsequent baseline neuronal response.

Language: Английский

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Automatic landmarking identifies new loci associated with face morphology and implicates Neanderthal introgression in human nasal shape

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: May 8, 2023

Abstract We report a genome-wide association study of facial features in >6000 Latin Americans based on automatic landmarking 2D portraits and testing for with inter-landmark distances. detected significant associations (P-value <5 × 10 −8 ) at 42 genome regions, nine which have been previously reported. In follow-up analyses, 26 the 33 novel regions replicate East Asians, Europeans, or Africans, one mouse homologous region influences craniofacial morphology mice. The 1q32.3 shows introgression from Neanderthals we find that introgressed tract increases nasal height (consistent differentiation between modern humans). Novel include candidate genes regulatory elements implicated development, show preferential transcription cranial neural crest cells. automated approach used here should simplify collection large samples across world, facilitating cosmopolitan characterization genetics features.

Language: Английский

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Aging alters mechanisms underlying voluntary movements in spinal motor neurons of mice, primates, and humans

JCI Insight, Journal Year: 2023, Volume and Issue: 8(9)

Published: May 7, 2023

Spinal motor neurons have been implicated in the loss of function that occurs with advancing age. However, cellular and molecular mechanisms impair these during aging remain unknown. Here, we show do not die old female male mice, rhesus monkeys, humans. Instead, selectively progressively shed excitatory synaptic inputs throughout soma dendritic arbor aging. Thus, aged contain a circuitry reduced ratio to inhibitory synapses may be responsible for diminished ability activate commence movements. An examination neuron translatome (ribosomal transcripts) mice reveals genes pathways roles glia-mediated pruning, inflammation, axonal regeneration, oxidative stress are upregulated neurons. Some also found altered affected amyotrophic lateral sclerosis (ALS) responding axotomy, demonstrating under significant stress. Our findings could serve as therapeutic targets preserve

Language: Английский

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Activation of ATF3 via the integrated stress response pathway regulates innate immune response to restrict Zika virus

Journal of Virology, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 30, 2024

ABSTRACT Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects of ZIKV infection arise in part from the triggering cellular stress pathways perturbing transcriptional programs. To date, underlying mechanisms control directing viral restriction virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) stress-induced effector modulates expression genes involved myriad processes, including inflammation antiviral responses, to restore homeostasis. While ATF3 known be upregulated during infection, mode by which activated, specific role unknown. In this study, we show via inhibitor RNA interference approaches initiates integrated response pathway activate ATF4 turn induces expression. Additionally, using CRISPR-Cas9 system delete ATF3, found acts limit gene A549 cells. We also determined enhances such as STAT1 other components innate immunity induce an ATF3-dependent anti-ZIKV response. Our study reveals crosstalk between immune highlights important for establishing effect infection. IMPORTANCE co-opts support processes reprogram host profile. Such viral-directed changes pro- or anti-viral outcomes remain previously showed transcription factor, significantly ZIKV-infected mammalian cells, along with genes. now define intracellular responsible activation elucidate impact on stimulates antagonize This establishes link viral-induced regulation defense thus expands our knowledge virus-mediated interferon-stimulated

Language: Английский

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ATF3 Knockdown Exacerbates Astrocyte Activation by Inhibiting Phosphorylation of Drp1 in Ischemic Stroke

Biologics, Journal Year: 2025, Volume and Issue: Volume 19, P. 15 - 29

Published: Feb. 1, 2025

Introduction: ATF3, a stress-induced transcription factor, has been implicated in the injury processes of various cell types, including neurons. It is recognized as common marker for neuronal damage following neurotrauma. However, its role other types glial cells, particularly astrocytes, response to ischemic remains unclear. Mitochondrial dysfunction key factor pathogenesis stroke, and impaired mitochondrial function astrocytes associated with astrocyte activation. This study aimed explore relationship between stroke investigate how ATF3 regulates activation context injury. Methods: In transient middle cerebral artery occlusion (tMCAO) mouse model, we knocked down assessed infarct size, motor deficits, activation, damage. vitro, used oxygen-glucose deprivation reoxygenation (OGD-R) simulate ischemia evaluated impact knockdown on function. Results: exacerbated vivo, increased depletion worsened interacted Drp1 via Akt2, inhibiting fission protecting astrocytes. Conclusion: protects highlighting potential therapeutic target recovery. Keywords: activating 3, acute AIS, dysfunction, dynamics-related protein 1, Drp1, threonine/serine kinase 2, Akt2

Language: Английский

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The transcription factor Jun is necessary for optic nerve regeneration in larval zebrafish

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(3), P. e0313534 - e0313534

Published: March 10, 2025

Damage to the axons of adult mammalian central nervous system (CNS) from traumatic injury or neurodegenerative diseases often results in permanent loss function due failure regenerate. Zebrafish, however, can express regeneration-associated genes revert CNS neurons a growth-competent state and regenerate damaged functionality. An established model for axon regeneration is optic nerve zebrafish, where it was previously shown that thousands are temporally expressed during time course. It likely hubs key transcription factors, rather than individual factors regulate temporal clusters expression after facilitate cell survival, regrowth, synaptic targeting brain. One factor interest orchestrating jun . However, remains unclear if progress without Jun. To test this, transgenic zebrafish line developed heat-shock inducible dominant negative Induction Jun downregulated endogenous larvae with functional knockdown demonstrated impaired retinal ganglion regeneration. Analysis select putative target genes, be upregulated regeneration, knockdown, atf3 ascl1a were significantly downregulated, sox11a at distinct points. These position as regulator successful further distinguish program development, advance our knowledge formation future therapies treat damage.

Language: Английский

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The Dynamics of Nerve Degeneration and Regeneration in a Healthy Milieu and in Diabetes

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(20), P. 15241 - 15241

Published: Oct. 16, 2023

Appropriate animal models, mimicking conditions of both health and disease, are needed to understand not only the biology physiology neurons other cells under normal but also stress conditions, like nerve injuries neuropathy. In such understanding how genes different factors activated through well-orchestrated programs in related is crucial. Knowledge about key players associated with regeneration intended for axonal outgrowth, migration Schwann respect suitable substrates, invasion macrophages, appropriate conditioning extracellular matrix, activation fibroblasts, formation endothelial blood vessels, healthy diabetic relevant. physical chemical attractions repulsions an optimal directed investigated various injury repair/reconstruction models using rat relevant glucose levels. Understanding dynamic processes constantly occurring neuropathies, neuropathy, concomitant degeneration regeneration, requires advanced technology bioinformatics integrated view behavior cell types based on genomics, transcriptomics, proteomics, imaging at visualization Single-cell-transcriptional profile analysis may reveal any heterogeneity among peripheral nerves disease.

Language: Английский

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Bulk RNA-seq conjoined with ScRNA-seq analysis reveals the molecular characteristics of nucleus pulposus cell ferroptosis in rat aging intervertebral discs

Arthritis Research & Therapy, Journal Year: 2025, Volume and Issue: 27(1)

Published: April 17, 2025

Recently, several studies have reported that nucleus pulposus (NP) cell ferroptosis plays a key role in IDD. However, the characteristics and molecular mechanisms of subsets involved remain unclear. We aimed to define factors driving ferroptosis, ferroptotic NP cells during The accumulation iron ions tissues rats caudal intervertebral discs (IVDs) was determined by Prussian blue staining. Fluorescent probe Undecanoyl Boron Dipyrromethene (C11-BODIPY) lipid peroxidation product 4-Hydroxynonenal (4-HNE) staining were performed assess level cells. differentially expressed genes with aging overlapped FerrDB database screen associated aging-related In addition, single sequencing (ScRNA-seq) used map cells, further identify subsets, as well their crucial drivers. Finally, cluster analysis marker Histological showed that, compared 10 months old (10M-old) group, increased 20 (20M-old) rats, also enhanced. 15 related IDD selected cross-enrichment. ScRNA-seq identified 14 tissue among which number ratio 5 reduced, intracellular signaling pathways significantly enriched, accompanied enhanced peroxidation. Notably, ranking up-regulation fold genes, we found Atf3 always present within TOP2 these five suggests it is factor ferroptosis. cross-enrichment fluorescence colocalization revealed Rps6 +/Cxcl1- common feature subsets. This study reveals ATF3 driver IDD, These findings provide evidence theoretical support for subsequent targeted intervention directions preventing delaying

Language: Английский

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Zebrafish optic nerve injury results in systemic retinal ganglion cell dedifferentiation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Abstract Retinal ganglion cells (RGCs) are the sole projection neurons connecting retina to brain and therefore play a critical role in vision. Death of RGCs during glaucoma, optic neuropathies after ocular trauma results irreversible loss vision as do not regenerate human eye. Moreover, there no FDA approved therapies that prevent RGC death and/or promote survival diseased or injured There is need better understand molecular underpinnings neuroprotection develop effective therapeutic approaches preserve damaged RGCs. Unlike mammals, zebrafish resilient nerve injury, even complete transection nerve. Here, we leveraged this unique model utilized single-cell RNA sequencing characterize responses injury identify putative neuroprotective regenerative pathways. heterogeneous studies mice have shown differential resiliency across subtypes. Our demonstrated all subtypes zebrafish. Quantifying changes gene expression revealed upregulation progenitor markers well distinct early late phases response. This shift causes injury-responsive resemble subtype 3, low frequency population endogenous immature normally maintained wild-type, uninjured adult retina. A similar but restricted transcriptomic response contralateral eye was also detected, highlighting systemic unilateral injury. Taken together, these demonstrate dedifferentiate may be novel mechanism mediating their cell capabilities. Author Summary connect essential for Their conditions like affecting over 70 million people worldwide, leads permanent blindness, with FDA-approved treatments it. In study, used next-generation technologies at level. We discovered survive damage by temporarily shifting into less mature state, resembling rare found animals. identified many genes whose RGCs, work significant because our detailed characterization identifies dedifferentiation an response, possibly important axon regrowth. The pathways potential targets enable

Language: Английский

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