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Purpose: The Retinal Ganglion Cell (RGC) Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium was founded in 2021 to help address the numerous scientific and clinical obstacles that impede development of vision-restorative treatments for patients with optic neuropathies. The goals of the RReSTORe consortium are: (1) to define and prioritize the most critical challenges and questions related to RGC regeneration; (2) to brainstorm innovative tools and experimental approaches to meet these challenges; and (3) to foster opportunities for collaborative scientific research among diverse investigators. Design and Participants: The RReSTORe consortium currently includes > 220 members spanning all career stages worldwide and is directed by an organizing committee comprised of 15 leading scientists and physician-scientists of diverse backgrounds. Methods: Herein, we describe the structure and organization of the RReSTORe consortium, its activities to date, and the perceived impact that the consortium has had on the field based on a survey of participants. Results: In addition to helping propel the field of regenerative medicine as applied to optic neuropathies, the RReSTORe consortium serves as a framework for developing large collaborative groups aimed at tackling audacious goals that may be expanded beyond ophthalmology and vision science. Conclusions: The development of innovative interventions capable of restoring vision for patients suffering from optic neuropathy would be transformative for the ophthalmology field, and may set the stage for functional restoration in other central nervous system disorders. By coordinating large-scale, international collaborations among scientists with diverse and complementary expertise, we are confident that the RReSTORe consortium will help to accelerate the field toward clinical translation. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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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.
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Doenças do Nervo Óptico , Células Ganglionares da Retina , Animais , Humanos , Retina , Encéfalo , Diferenciação Celular , MamíferosRESUMO
The regulation of protein degradation is essential for maintaining the appropriate environment to coordinate complex cell signaling events and to promote cellular remodeling. The Autophagy linked FYVE protein (Alfy), previously identified as a molecular scaffold between the ubiquitinated cargo and the autophagic machinery, is highly expressed in the developing central nervous system, indicating that this pathway may have yet unexplored roles in neurodevelopment. To examine this possibility, we used mouse genetics to eliminate Alfy expression. We report that this evolutionarily conserved protein is required for the formation of axonal tracts throughout the brain and spinal cord, including the formation of the major forebrain commissures. Consistent with a phenotype reflecting a failure in axon guidance, the loss of Alfy in mice disrupts localization of glial guidepost cells, and attenuates axon outgrowth in response to Netrin-1. These findings further support the growing indication that macroautophagy plays a key role in the developing CNS.
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Encéfalo/embriologia , Vias Neurais/embriologia , Neurônios/fisiologia , Proteínas de Transporte Vesicular/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas Relacionadas à Autofagia , Técnicas de Inativação de Genes , Camundongos Endogâmicos C57BLRESUMO
Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.
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Axônios/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal , Potenciais de Ação , Animais , Animais Recém-Nascidos , Proliferação de Células , Células Cultivadas , AMP Cíclico/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Dendritos/metabolismo , Dendritos/fisiologia , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/metabolismo , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Imuno-Histoquímica , Potenciação de Longa Duração , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fibras Musgosas Hipocampais/metabolismo , Proteínas do Tecido Nervoso/genética , Neurogênese , Neurônios/citologia , Neurônios/metabolismo , Neurônios/fisiologia , Técnicas de Patch-ClampRESUMO
Emerging evidence supports the concept that T helper type 17 (T(H)17) cells, in addition to mediating autoimmunity, have key roles in mucosal immunity against extracellular pathogens. Interleukin-22 (IL-22) and IL-17A are both effector cytokines produced by the T(H)17 lineage, and both were crucial for maintaining local control of the Gram-negative pulmonary pathogen, Klebsiella pneumoniae. Although both cytokines regulated CXC chemokines and granulocyte colony-stimulating factor production in the lung, only IL-22 increased lung epithelial cell proliferation and increased transepithelial resistance to injury. These data support the concept that the T(H)17 cell lineage and its effector molecules have evolved to effect host defense against extracellular pathogens at mucosal sites.
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Imunidade nas Mucosas/imunologia , Interleucinas/imunologia , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/imunologia , Animais , Células Cultivadas , Quimiocinas/metabolismo , Fibrose Cística/imunologia , Fibrose Cística/patologia , Células Epiteliais/metabolismo , Humanos , Interleucina-17/imunologia , Interleucina-23/imunologia , Interleucinas/metabolismo , Klebsiella pneumoniae/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Linfonodos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Neutralização , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Mucosa Respiratória/citologia , Baço/microbiologia , Linfócitos T/imunologia , Regulação para Cima , Interleucina 22RESUMO
Ena/vasodilator-stimulated phosphoprotein (VASP) proteins regulate the geometry of the actin cytoskeleton, thereby influencing cell morphology and motility. Analysis of invertebrate mutants implicates Ena/VASP function in several actin-dependent processes such as axon and dendritic guidance, cell migration, and dorsal closure. In vertebrates, genetic analysis of Ena/VASP function is hindered by the broad and overlapping expression of the three highly related family members Mena (Mammalian enabled), VASP, and EVL (Ena-VASP like). Mice deficient in either Mena or VASP exhibit subtle defects in forebrain commissure formation and platelet aggregation, respectively. In this study, we investigated the consequence of deleting both Mena and VASP. Mena-/-VASP-/- double mutants die perinatally and display defects in neurulation, craniofacial structures, and the formation of several fiber tracts in the CNS and peripheral nervous system.
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Anormalidades Múltiplas/genética , Moléculas de Adesão Celular/fisiologia , Proteínas do Citoesqueleto/fisiologia , Fosfoproteínas/fisiologia , Anormalidades Múltiplas/embriologia , Actinas/fisiologia , Agenesia do Corpo Caloso , Animais , Axônios/patologia , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Movimento Celular , Corpo Caloso/embriologia , Anormalidades Craniofaciais/embriologia , Anormalidades Craniofaciais/genética , Cruzamentos Genéticos , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Citoesqueleto/fisiologia , Citoesqueleto/ultraestrutura , Desenvolvimento Embrionário/genética , Feminino , Genes Letais , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos , Morfogênese , Família Multigênica , Sistema Nervoso/embriologia , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/genética , Quiasma Óptico/anormalidades , Quiasma Óptico/embriologia , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Prosencéfalo/anormalidades , Nervos Espinhais/anormalidades , Nervos Espinhais/embriologiaRESUMO
While generating transgenic lines, transgene-linked mutations can occur, which are caused by an insertional mutation at a given locus. More rarely, mutations unlinked to the transgene insertion site are observed. In the process of generating a mouse overexpressing the enzyme tyrosinase, we have obtained one transgenic line that appears to carry a semidominant insertional mutation at the Gli3 (extra toes) locus, characterized by polydactyly and skeletal malformations. Additionally, the transgenic line contained a second mutation, Crc (circletail), which appears to be unlinked to the transgene insertion site. Heterozygous Crc mice are incompletely penetrant for a circled-tail phenotype, while all homozygous Crc/Crc mice die at birth of a severe neural tube defect (craniorachischisis). Anatomical evidence from a Crc/Crc; Gli3/+ fetus indicates that these two genes may interact.