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Cell Jan 2024Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with...
Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1 expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPβ was dependent on JAK1 in the vagus nerve, and CGRPβ suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.
Topics: Animals; Humans; Mice; Cytokines; Dermatitis, Atopic; Immunity, Innate; Inflammation; Lung; Lymphocytes; Sensory Receptor Cells
PubMed: 38134932
DOI: 10.1016/j.cell.2023.11.027 -
Molecular Aspects of Medicine Aug 2023Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output... (Review)
Review
Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons of the retina. Glaucoma is the most common cause of irreversible blindness and affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, and elevated intraocular pressure. Current strategies only target intraocular pressure management and do not directly target the neurodegenerative processes occurring at the level of the retinal ganglion cell. Despite strategies to manage intraocular pressure, as many as 40% of glaucoma patients progress to blindness in at least one eye during their lifetime. As such, neuroprotective strategies that target the retinal ganglion cell and these neurodegenerative processes directly are of great therapeutic need. This review will cover the recent advances from basic biology to on-going clinical trials for neuroprotection in glaucoma covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, and neuroinflammation. With an increased understanding of both the basic and clinical mechanisms of the disease, we are closer than ever to a neuroprotective strategy for glaucoma.
Topics: Humans; Intraocular Pressure; Neuroprotection; Neurodegenerative Diseases; Glaucoma; Retinal Ganglion Cells; Blindness
PubMed: 37331129
DOI: 10.1016/j.mam.2023.101193 -
Neuron Jul 2023Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many...
Vagal sensory neurons monitor mechanical and chemical stimuli in the gastrointestinal tract. Major efforts are underway to assign physiological functions to the many distinct subtypes of vagal sensory neurons. Here, we use genetically guided anatomical tracing, optogenetics, and electrophysiology to identify and characterize vagal sensory neuron subtypes expressing Prox2 and Runx3 in mice. We show that three of these neuronal subtypes innervate the esophagus and stomach in regionalized patterns, where they form intraganglionic laminar endings. Electrophysiological analysis revealed that they are low-threshold mechanoreceptors but possess different adaptation properties. Lastly, genetic ablation of Prox2 and Runx3 neurons demonstrated their essential roles for esophageal peristalsis in freely behaving mice. Our work defines the identity and function of the vagal neurons that provide mechanosensory feedback from the esophagus to the brain and could lead to better understanding and treatment of esophageal motility disorders.
Topics: Animals; Mice; Core Binding Factor Alpha 3 Subunit; Esophagus; Gastrointestinal Motility; Homeodomain Proteins; Mechanoreceptors; Neurons, Afferent; Sensory Receptor Cells; Stomach; Vagus Nerve
PubMed: 37192624
DOI: 10.1016/j.neuron.2023.04.025 -
Cell Aug 2023The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology...
The properties of dorsal root ganglia (DRG) neurons that innervate the distal colon are poorly defined, hindering our understanding of their roles in normal physiology and gastrointestinal (GI) disease. Here, we report genetically defined subsets of colon-innervating DRG neurons with diverse morphologic and physiologic properties. Four colon-innervating DRG neuron populations are mechanosensitive and exhibit distinct force thresholds to colon distension. The highest threshold population, selectively labeled using Bmpr1b genetic tools, is necessary and sufficient for behavioral responses to high colon distension, which is partly mediated by the mechanosensory ion channel Piezo2. This Aδ-HTMR population mediates behavioral over-reactivity to colon distension caused by inflammation in a model of inflammatory bowel disease. Thus, like cutaneous DRG mechanoreceptor populations, colon-innervating mechanoreceptors exhibit distinct anatomical and physiological properties and tile force threshold space, and genetically defined colon-innervating HTMRs mediate pathophysiological responses to colon distension, revealing a target population for therapeutic intervention.
Topics: Ganglia, Spinal; Mechanoreceptors; Colon; Neurons; Skin
PubMed: 37541195
DOI: 10.1016/j.cell.2023.07.007 -
Cell Mar 2024Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG...
Dorsal root ganglia (DRG) somatosensory neurons detect mechanical, thermal, and chemical stimuli acting on the body. Achieving a holistic view of how different DRG neuron subtypes relay neural signals from the periphery to the CNS has been challenging with existing tools. Here, we develop and curate a mouse genetic toolkit that allows for interrogating the properties and functions of distinct cutaneous targeting DRG neuron subtypes. These tools have enabled a broad morphological analysis, which revealed distinct cutaneous axon arborization areas and branching patterns of the transcriptionally distinct DRG neuron subtypes. Moreover, in vivo physiological analysis revealed that each subtype has a distinct threshold and range of responses to mechanical and/or thermal stimuli. These findings support a model in which morphologically and physiologically distinct cutaneous DRG sensory neuron subtypes tile mechanical and thermal stimulus space to collectively encode a wide range of natural stimuli.
Topics: Animals; Mice; Ganglia, Spinal; Sensory Receptor Cells; Single-Cell Gene Expression Analysis; Skin
PubMed: 38442711
DOI: 10.1016/j.cell.2024.02.006 -
Progress in Retinal and Eye Research Jul 2023Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by a slow, progressive, and multifactorial degeneration of retinal ganglion cells... (Review)
Review
Glaucoma is a leading cause of irreversible blindness worldwide and is characterized by a slow, progressive, and multifactorial degeneration of retinal ganglion cells (RGCs) and their axons, resulting in vision loss. Despite its high prevalence in individuals 60 years of age and older, the causing factors contributing to glaucoma progression are currently not well characterized. Intraocular pressure (IOP) is the only proven treatable risk factor. However, lowering IOP is insufficient for preventing disease progression. One of the significant interests in glaucoma pathogenesis is understanding the structural and functional impairment of mitochondria in RGCs and their axons and synapses. Glaucomatous risk factors such as IOP elevation, aging, genetic variation, neuroinflammation, neurotrophic factor deprivation, and vascular dysregulation, are potential inducers for mitochondrial dysfunction in glaucoma. Because oxidative phosphorylation stress-mediated mitochondrial dysfunction is associated with structural and functional impairment of mitochondria in glaucomatous RGCs, understanding the underlying mechanisms and relationship between structural and functional alterations in mitochondria would be beneficial to developing mitochondria-related neuroprotection in RGCs and their axons and synapses against glaucomatous neurodegeneration. Here, we review the current studies focusing on mitochondrial dynamics-based structural and functional alterations in the mitochondria of glaucomatous RGCs and therapeutic strategies to protect RGCs against glaucomatous neurodegeneration.
Topics: Humans; Retinal Ganglion Cells; Mitochondrial Dynamics; Glaucoma; Intraocular Pressure; Optic Nerve Diseases
PubMed: 36400670
DOI: 10.1016/j.preteyeres.2022.101136 -
Nature Biotechnology Dec 2023Organoids generated from human pluripotent stem cells provide experimental systems to study development and disease, but quantitative measurements across different...
Organoids generated from human pluripotent stem cells provide experimental systems to study development and disease, but quantitative measurements across different spatial scales and molecular modalities are lacking. In this study, we generated multiplexed protein maps over a retinal organoid time course and primary adult human retinal tissue. We developed a toolkit to visualize progenitor and neuron location, the spatial arrangements of extracellular and subcellular components and global patterning in each organoid and primary tissue. In addition, we generated a single-cell transcriptome and chromatin accessibility timecourse dataset and inferred a gene regulatory network underlying organoid development. We integrated genomic data with spatially segmented nuclei into a multimodal atlas to explore organoid patterning and retinal ganglion cell (RGC) spatial neighborhoods, highlighting pathways involved in RGC cell death and showing that mosaic genetic perturbations in retinal organoids provide insight into cell fate regulation.
Topics: Humans; Retina; Retinal Ganglion Cells; Pluripotent Stem Cells; Transcriptome; Organoids; Cell Differentiation
PubMed: 37156914
DOI: 10.1038/s41587-023-01747-2 -
Molecular Neurodegeneration Sep 2023Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited... (Review)
Review
Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.
Topics: Animals; Humans; Retinal Ganglion Cells; Optic Nerve Diseases; Retina; Brain; Cell Differentiation; Mammals
PubMed: 37735444
DOI: 10.1186/s13024-023-00655-y -
Neuron Aug 2023Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch,...
Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the potential of FM 1-43 by using it to identify novel PIEZO2-expressing urethral neurons that are engaged by urination. These data reveal that FM 1-43 is a functional probe for mechanosensitivity via PIEZO2 activation in vivo and will facilitate the characterization of known and novel mechanosensory processes in multiple organ systems.
Topics: Mice; Animals; Mechanotransduction, Cellular; Ion Channels; Sensory Receptor Cells; Pyridinium Compounds
PubMed: 37321223
DOI: 10.1016/j.neuron.2023.05.015