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1.
Cell Mol Life Sci ; 81(1): 47, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-38236305

RESUMEN

Type 2 diabetes mellitus is a global epidemic that due to its increasing prevalence worldwide will likely become the most common debilitating health condition. Even if diabetes is primarily a metabolic disorder, it is now well established that key aspects of the pathogenesis of diabetes are associated with nervous system alterations, including deleterious chronic inflammation of neural tissues, referred here as neuroinflammation, along with different detrimental glial cell responses to stress conditions and neurodegenerative features. Moreover, diabetes resembles accelerated aging, further increasing the risk of developing age-linked neurodegenerative disorders. As such, the most common and disabling diabetic comorbidities, namely diabetic retinopathy, peripheral neuropathy, and cognitive decline, are intimately associated with neurodegeneration. As described in aging and other neurological disorders, glial cell alterations such as microglial, astrocyte, and Müller cell increased reactivity and dysfunctionality, myelin loss and Schwann cell alterations have been broadly described in diabetes in both human and animal models, where they are key contributors to chronic noxious inflammation of neural tissues within the PNS and CNS. In this review, we aim to describe in-depth the common and unique aspects underlying glial cell changes observed across the three main diabetic complications, with the goal of uncovering shared glial cells alterations and common pathological mechanisms that will enable the discovery of potential targets to limit neuroinflammation and prevent neurodegeneration in all three diabetic complications. Diabetes and its complications are already a public health concern due to its rapidly increasing incidence, and thus its health and economic impact. Hence, understanding the key role that glial cells play in the pathogenesis underlying peripheral neuropathy, retinopathy, and cognitive decline in diabetes will provide us with novel therapeutic approaches to tackle diabetic-associated neurodegeneration.


Asunto(s)
Diabetes Mellitus Tipo 2 , Retinopatía Diabética , Enfermedades del Sistema Nervioso Periférico , Animales , Humanos , Enfermedades Neuroinflamatorias , Neuroglía , Inflamación
2.
PLoS Genet ; 18(6): e1010224, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35666718

RESUMEN

How cell to cell interactions control local tissue growth to attain a species-specific organ size is a central question in developmental biology. The Drosophila Neural Cell Adhesion Molecule, Fasciclin 2, is expressed during the development of neural and epithelial organs. Fasciclin 2 is a homophilic-interaction protein that shows moderate levels of expression in the proliferating epithelia and high levels in the differentiating non-proliferative cells of imaginal discs. Genetic interactions and mosaic analyses reveal a cell autonomous requirement of Fasciclin 2 to promote cell proliferation in imaginal discs. This function is mediated by the EGFR, and indirectly involves the JNK and Hippo signaling pathways. We further show that Fasciclin 2 physically interacts with EGFR and that, in turn, EGFR activity promotes the cell autonomous expression of Fasciclin 2 during imaginal disc growth. We propose that this auto-stimulatory loop between EGFR and Fasciclin 2 is at the core of a cell to cell interaction mechanism that controls the amount of intercalary growth in imaginal discs.


Asunto(s)
Proteínas de Drosophila , Discos Imaginales , Animales , Proliferación Celular/genética , Drosophila/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Receptores ErbB/genética , Receptores de Péptidos de Invertebrados/genética , Alas de Animales
3.
Glia ; 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39149866

RESUMEN

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease characterized by motor neuron death and distal axonopathy. Despite its clinical severity and profound impact in the patients and their families, many questions about its pathogenesis remain still unclear, including the role of Schwann cells and axon-glial signaling in disease progression. Upon axonal injury, upregulation of JUN transcription factor promotes Schwann cell reprogramming into a repair phenotype that favors axon regrowth and neuronal survival. To study the potential role of repair Schwann cells on motoneuron survival in amyotrophic lateral sclerosis, we generated a mouse line that over-expresses JUN in the Schwann cells of the SOD1G93A mutant, a mouse model of this disease. Then, we explored disease progression by evaluating survival, motor performance and histology of peripheral nerves and spinal cord of these mice. We found that Schwann cell JUN overexpression does not prevent axon degeneration neither motor neuron death in the SOD1G93A mice. Instead, it induces a partial demyelination of medium and large size axons, worsening motor performance and resulting in more aggressive disease phenotype.

4.
Immunol Cell Biol ; 101(1): 25-35, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36427276

RESUMEN

The interaction between immune and stem cells has proven essential for homeostasis and regeneration in a wide range of tissues. However, because the central nervous system was long considered an immune-privileged organ, its immune-stem cell axis was not deeply investigated until recently. Research has shown that oligodendrocyte progenitor cells (OPCs), a highly abundant population of adult brain stem cells, establish bidirectional interactions with the immune system. Here, we provide an overview of the interactions that OPCs have with tissue-resident and recruited immune cells, paying particular attention to the role they play in myelin regeneration and neuroinflammation. We highlight the described role of OPCs as key active players in neuroinflammation, overriding the previous concept that OPCs are mere recipients of immune signals. Understanding the mechanisms behind this bidirectional interaction holds great potential for the development of novel therapeutic approaches limiting neuroinflammation and promoting myelin repair. A better understanding of the central nervous system's immune-stem cell axis will also be key for tackling two important features shared across neurodegenerative diseases, neuroinflammation and myelin loss.


Asunto(s)
Células Precursoras de Oligodendrocitos , Humanos , Células Precursoras de Oligodendrocitos/fisiología , Oligodendroglía , Enfermedades Neuroinflamatorias , Sistema Nervioso Central , Células Madre , Diferenciación Celular
5.
Int J Mol Sci ; 23(6)2022 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-35328416

RESUMEN

The peripheral nervous system (PNS) has a remarkable regenerative capacity in comparison to the central nervous system (CNS), a phenomenon that is impaired during ageing. The ability of PNS axons to regenerate after injury is due to Schwann cells (SC) being reprogrammed into a repair phenotype called Repair Schwann cells. These repair SCs are crucial for supporting axonal growth after injury, myelin degradation in a process known as myelinophagy, neurotropic factor secretion, and axonal growth guidance through the formation of Büngner bands. After regeneration, repair SCs can remyelinate newly regenerated axons and support nonmyelinated axons. Increasing evidence points to an epigenetic component in the regulation of repair SC gene expression changes, which is necessary for SC reprogramming and regeneration. One of these epigenetic regulations is histone acetylation by histone acetyl transferases (HATs) or histone deacetylation by histone deacetylases (HDACs). In this review, we have focused particularly on three HDAC classes (I, II, and IV) that are Zn2+-dependent deacetylases. These HDACs are important in repair SC biology and remyelination after PNS injury. Another key aspect explored in this review is HDAC genetic compensation in SCs and novel HDAC inhibitors that are being studied to improve nerve regeneration.


Asunto(s)
Histona Desacetilasas , Histonas , Axones/metabolismo , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Regeneración Nerviosa/fisiología , Sistema Nervioso Periférico/metabolismo , Células de Schwann/metabolismo
6.
J Neurosci ; 37(16): 4255-4269, 2017 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-28320842

RESUMEN

After nerve injury, Schwann cells convert to a phenotype specialized to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signaling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signaling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers, including Shh, GDNF, and BDNF. Because Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population.SIGNIFICANCE STATEMENT Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is that, during the slow growth of axons through the proximal parts of injured nerves repair, Schwann cells gradually lose regeneration-supporting features and eventually die. Identification of signals that sustain repair cells is therefore an important goal. We have found that in mice the transcription factor STAT3 protects these cells from death and contributes to maintaining the molecular and morphological repair phenotype that promotes axonal regeneration. Defining the molecular mechanisms that maintain repair Schwann cells is an essential step toward developing therapeutic strategies that improve nerve regeneration and functional recovery.


Asunto(s)
Regeneración Nerviosa , Traumatismos de los Nervios Periféricos/metabolismo , Fenotipo , Factor de Transcripción STAT3/genética , Células de Schwann/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Masculino , Ratones , Factor de Transcripción STAT3/metabolismo , Células de Schwann/citología
7.
J Neurosci ; 37(37): 9086-9099, 2017 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-28904214

RESUMEN

There is consensus that, distal to peripheral nerve injury, myelin and Remak cells reorganize to form cellular columns, Bungner's bands, which are indispensable for regeneration. However, knowledge of the structure of these regeneration tracks has not advanced for decades and the structure of the cells that form them, denervated or repair Schwann cells, remains obscure. Furthermore, the origin of these cells from myelin and Remak cells and their ability to give rise to myelin cells after regeneration has not been demonstrated directly, although these conversions are believed to be central to nerve repair. Using genetic lineage-tracing and scanning-block face electron microscopy, we show that injury of sciatic nerves from mice of either sex triggers extensive and unexpected Schwann cell elongation and branching to form long, parallel processes. Repair cells are 2- to 3-fold longer than myelin and Remak cells and 7- to 10-fold longer than immature Schwann cells. Remarkably, when repair cells transit back to myelinating cells, they shorten ∼7-fold to generate the typically short internodes of regenerated nerves. The present experiments define novel morphological transitions in injured nerves and show that repair Schwann cells have a cell-type-specific structure that differentiates them from other cells in the Schwann cell lineage. They also provide the first direct evidence using genetic lineage tracing for two basic assumptions in Schwann cell biology: that myelin and Remak cells generate the elongated cells that build Bungner bands in injured nerves and that such cells can transform to myelin cells after regeneration.SIGNIFICANCE STATEMENT After injury to peripheral nerves, the myelin and Remak Schwann cells distal to the injury site reorganize and modify their properties to form cells that support the survival of injured neurons, promote axon growth, remove myelin-associated growth inhibitors, and guide regenerating axons to their targets. We show that the generation of these repair-supportive Schwann cells involves an extensive cellular elongation and branching, often to form long, parallel processes. This generates a distinctive repair cell morphology that is favorable for the formation of the regeneration tracks that are essential for nerve repair. Remyelination, conversely, involves a striking cell shortening to form the typical short myelin cells of regenerated nerves. We also provide evidence for direct lineage relationships between: (1) repair cells and myelin and Remak cells of uninjured nerves and (2) remyelinating cells in regenerated nerves.


Asunto(s)
Vaina de Mielina/metabolismo , Regeneración Nerviosa/fisiología , Proyección Neuronal , Traumatismos de los Nervios Periféricos/patología , Traumatismos de los Nervios Periféricos/fisiopatología , Células de Schwann/patología , Animales , Femenino , Masculino , Ratones , Ratones Transgénicos
8.
J Neurosci ; 37(50): 12297-12313, 2017 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-29109239

RESUMEN

Schwann cell c-Jun is implicated in adaptive and maladaptive functions in peripheral nerves. In injured nerves, this transcription factor promotes the repair Schwann cell phenotype and regeneration and promotes Schwann-cell-mediated neurotrophic support in models of peripheral neuropathies. However, c-Jun is associated with tumor formation in some systems, potentially suppresses myelin genes, and has been implicated in demyelinating neuropathies. To clarify these issues and to determine how c-Jun levels determine its function, we have generated c-Jun OE/+ and c-Jun OE/OE mice with graded expression of c-Jun in Schwann cells and examined these lines during development, in adulthood, and after injury using RNA sequencing analysis, quantitative electron microscopic morphometry, Western blotting, and functional tests. Schwann cells are remarkably tolerant of elevated c-Jun because the nerves of c-Jun OE/+ mice, in which c-Jun is elevated ∼6-fold, are normal with the exception of modestly reduced myelin thickness. The stronger elevation of c-Jun in c-Jun OE/OE mice is, however, sufficient to induce significant hypomyelination pathology, implicating c-Jun as a potential player in demyelinating neuropathies. The tumor suppressor P19ARF is strongly activated in the nerves of these mice and, even in aged c-Jun OE/OE mice, there is no evidence of tumors. This is consistent with the fact that tumors do not form in injured nerves, although they contain proliferating Schwann cells with strikingly elevated c-Jun. Furthermore, in crushed nerves of c-Jun OE/+ mice, where c-Jun levels are overexpressed sufficiently to accelerate axonal regeneration, myelination and function are restored after injury.SIGNIFICANCE STATEMENT In injured and diseased nerves, the transcription factor c-Jun in Schwann cells is elevated and variously implicated in controlling beneficial or adverse functions, including trophic Schwann cell support for neurons, promotion of regeneration, tumorigenesis, and suppression of myelination. To analyze the functions of c-Jun, we have used transgenic mice with graded elevation of Schwann cell c-Jun. We show that high c-Jun elevation is a potential pathogenic mechanism because it inhibits myelination. Conversely, we did not find a link between c-Jun elevation and tumorigenesis. Modest c-Jun elevation, which is beneficial for regeneration, is well tolerated during Schwann cell development and in the adult and is compatible with restoration of myelination and nerve function after injury.


Asunto(s)
Dosificación de Gen , Vaina de Mielina/fisiología , Regeneración Nerviosa/fisiología , Proteínas del Tejido Nervioso/fisiología , Proteínas Proto-Oncogénicas c-jun/fisiología , Células de Schwann/metabolismo , Animales , Axones/patología , Núcleo Celular/metabolismo , Transformación Celular Neoplásica , Femenino , Perfilación de la Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de la Mielina/biosíntesis , Proteínas de la Mielina/genética , Vaina de Mielina/ultraestructura , Compresión Nerviosa , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Proteínas Proto-Oncogénicas c-jun/biosíntesis , Proteínas Proto-Oncogénicas c-jun/genética , ARN Mensajero/biosíntesis , Recuperación de la Función , Nervio Ciático/lesiones , Nervio Ciático/patología
9.
Artículo en Inglés | MEDLINE | ID: mdl-38199866

RESUMEN

Peripheral nerves exist in a stable state in adulthood providing a rapid bidirectional signaling system to control tissue structure and function. However, following injury, peripheral nerves can regenerate much more effectively than those of the central nervous system (CNS). This multicellular process is coordinated by peripheral glia, in particular Schwann cells, which have multiple roles in stimulating and nurturing the regrowth of damaged axons back to their targets. Aside from the repair of damaged nerves themselves, nerve regenerative processes have been linked to the repair of other tissues and de novo innervation appears important in establishing an environment conducive for the development and spread of tumors. In contrast, defects in these processes are linked to neuropathies, aging, and pain. In this review, we focus on the role of peripheral glia, especially Schwann cells, in multiple aspects of nerve regeneration and discuss how these findings may be relevant for pathologies associated with these processes.


Asunto(s)
Regeneración Nerviosa , Células de Schwann , Células de Schwann/fisiología , Regeneración Nerviosa/fisiología , Humanos , Animales , Nervios Periféricos/fisiología , Axones/fisiología
10.
Elife ; 132024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38192199

RESUMEN

Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls. AxCaliber is sensitive to acute axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the targeted tract, which correlated with neurofilament staining. Electron microscopy confirmed that increased mean axonal diameter is associated with acute axonal pathology. In humans with multiple sclerosis, we uncovered a diffuse increase in mean axonal caliber in most areas of the normal-appearing white matter, preferentially affecting patients with short disease duration. Our results demonstrate that MRI-based axonal diameter mapping is a sensitive and specific imaging biomarker that links noninvasive imaging contrasts with the underlying biological substrate, uncovering generalized axonal damage in multiple sclerosis as an early event.


Asunto(s)
Esclerosis Múltiple , Humanos , Animales , Ratas , Esclerosis Múltiple/diagnóstico por imagen , Axones , Imagen por Resonancia Magnética , Encéfalo , Difusión
11.
EMBO Mol Med ; 15(12): e17907, 2023 Dec 07.
Artículo en Inglés | MEDLINE | ID: mdl-37860842

RESUMEN

Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c-Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c-Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c-Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c-Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.


Asunto(s)
Traumatismos de los Nervios Periféricos , Humanos , Anciano , Traumatismos de los Nervios Periféricos/terapia , Traumatismos de los Nervios Periféricos/genética , Traumatismos de los Nervios Periféricos/metabolismo , Células de Schwann/metabolismo , Envejecimiento , Regulación de la Expresión Génica , Desnervación
12.
Front Cell Neurosci ; 17: 1158388, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37091921

RESUMEN

Since SARM1 mutations have been identified in human neurological disease, SARM1 inhibition has become an attractive therapeutic strategy to preserve axons in a variety of disorders of the peripheral (PNS) and central nervous system (CNS). While SARM1 has been extensively studied in neurons, it remains unknown whether SARM1 is present and functional in myelinating glia? This is an important question to address. Firstly, to identify whether SARM1 dysfunction in other cell types in the nervous system may contribute to neuropathology in SARM1 dependent diseases? Secondly, to ascertain whether therapies altering SARM1 function may have unintended deleterious impacts on PNS or CNS myelination? Surprisingly, we find that oligodendrocytes express sarm1 mRNA in the zebrafish spinal cord and that SARM1 protein is readily detectable in rodent oligodendrocytes in vitro and in vivo. Furthermore, activation of endogenous SARM1 in cultured oligodendrocytes induces rapid cell death. In contrast, in peripheral glia, SARM1 protein is not detectable in Schwann cells and satellite glia in vivo and sarm1/Sarm1 mRNA is detected at very low levels in Schwann cells, in vivo, in zebrafish and mouse. Application of specific SARM1 activators to cultured mouse Schwann cells does not induce cell death and nicotinamide adenine dinucleotide (NAD) levels remain unaltered suggesting Schwann cells likely contain no functionally relevant levels of SARM1. Finally, we address the question of whether SARM1 is required for myelination or myelin maintenance. In the zebrafish and mouse PNS and CNS, we show that SARM1 is not required for initiation of myelination and myelin sheath maintenance is unaffected in the adult mouse nervous system. Thus, strategies to inhibit SARM1 function to treat neurological disease are unlikely to perturb myelination in humans.

13.
Cell Metab ; 35(12): 2136-2152.e9, 2023 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-37989315

RESUMEN

The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.


Asunto(s)
Vaina de Mielina , Nervios Periféricos , Vaina de Mielina/metabolismo , Neuroglía , Células de Schwann/metabolismo , Regeneración Nerviosa/fisiología
14.
Elife ; 112022 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-35076395

RESUMEN

The class IIa histone deacetylases (HDACs) have pivotal roles in the development of different tissues. Of this family, Schwann cells express Hdac4, 5, and 7 but not Hdac9. Here, we show that a transcription factor regulated genetic compensatory mechanism within this family of proteins, blocks negative regulators of myelination ensuring peripheral nerve developmental myelination and remyelination after injury. Thus, when Hdac4 and 5 are knocked-out from Schwann cells in mice, a JUN-dependent mechanism induces the compensatory overexpression of Hdac7 permitting, although with a delay, the formation of the myelin sheath. When Hdac4, 5, and 7 are simultaneously removed, the myocyte-specific enhancer-factor d (MEF2D) binds to the promoter and induces the de novo expression of Hdac9, and although several melanocytic lineage genes are misexpressed and Remak bundle structure is disrupted, myelination proceeds after a long delay. Thus, our data unveil a finely tuned compensatory mechanism within the class IIa Hdac family, coordinated by distinct transcription factors, that guarantees the ability of Schwann cells to myelinate during development and remyelinate after nerve injury.


Asunto(s)
Regulación de la Expresión Génica/fisiología , Genes jun/genética , Histona Desacetilasas/genética , Nervios Periféricos/fisiología , Remielinización , Células de Schwann/metabolismo , Animales , Femenino , Histona Desacetilasas/metabolismo , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Masculino , Ratones
15.
Elife ; 102021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33475496

RESUMEN

After nerve injury, myelin and Remak Schwann cells reprogram to repair cells specialized for regeneration. Normally providing strong regenerative support, these cells fail in aging animals, and during chronic denervation that results from slow axon growth. This impairs axonal regeneration and causes significant clinical problems. In mice, we find that repair cells express reduced c-Jun protein as regenerative support provided by these cells declines during aging and chronic denervation. In both cases, genetically restoring Schwann cell c-Jun levels restores regeneration to control levels. We identify potential gene candidates mediating this effect and implicate Shh in the control of Schwann cell c-Jun levels. This establishes that a common mechanism, reduced c-Jun in Schwann cells, regulates success and failure of nerve repair both during aging and chronic denervation. This provides a molecular framework for addressing important clinical problems, suggesting molecular pathways that can be targeted to promote repair in the PNS.


Asunto(s)
Envejecimiento , Regeneración Nerviosa , Proteínas Proto-Oncogénicas c-jun/genética , Células de Schwann/metabolismo , Animales , Femenino , Masculino , Ratones , Proteínas Proto-Oncogénicas c-jun/metabolismo
16.
J Neurosci ; 29(36): 11304-15, 2009 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-19741137

RESUMEN

Type III neuregulins exposed on axon surfaces control myelination of the peripheral nervous system. It has been shown, for example, that threshold levels of type III beta1a neuregulin dictate not only the myelination fate of axons but also myelin thickness. Here we show that another neuregulin isoform, type III-beta3, plays a distinct role in myelination. Neuronal overexpression of this isoform in mice stimulates Schwann cell proliferation and dramatically enlarges peripheral nerves and ganglia-which come to resemble plexiform neurofibromas-but have no effect on myelin thickness. The nerves display other neurofibroma-like properties, such as abundant collagen fibrils and abundant dissociated Schwann cells that in some cases produce big tumors. Moreover, the organization of Remak bundles is dramatically altered; the small-caliber axons of each bundle are no longer segregated from one another within the cytoplasm of a nonmyelinating Schwann cell but instead are close packed and the whole bundle wrapped as a single unit, frequently by a compact myelin sheath. Because Schwann cell hyperproliferation and Remak bundle degeneration are early hallmarks of type I neurofibromatosis, we suggest that sustained activation of the neuregulin pathway in Remak bundles can contribute to neurofibroma development.


Asunto(s)
Axones/fisiología , Proliferación Celular , Vaina de Mielina/fisiología , Neurofibroma/metabolismo , Neuroglía/fisiología , Células de Schwann/fisiología , Animales , Animales Recién Nacidos , Femenino , Humanos , Péptidos y Proteínas de Señalización Intracelular/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neoplasias del Sistema Nervioso/metabolismo , Neoplasias del Sistema Nervioso/patología , Neurregulinas , Neurofibroma/patología , Neuroglía/patología , Embarazo , Células de Schwann/patología , Transducción de Señal/fisiología
17.
J Cell Biol ; 217(4): 1249-1268, 2018 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-29472387

RESUMEN

Schwann cells respond to cyclic adenosine monophosphate (cAMP) halting proliferation and expressing myelin proteins. Here we show that cAMP signaling induces the nuclear shuttling of the class IIa histone deacetylase (HDAC)-4 in these cells, where it binds to the promoter and blocks the expression of c-Jun, a negative regulator of myelination. To do it, HDAC4 does not interfere with the transcriptional activity of MEF2. Instead, by interacting with NCoR1, it recruits HDAC3 and deacetylates histone 3 in the promoter of c-Jun, blocking gene expression. Importantly, this is enough to up-regulate Krox20 and start Schwann cell differentiation program-inducing myelin gene expression. Using conditional knockout mice, we also show that HDAC4 together with HDAC5 redundantly contribute to activate the myelin transcriptional program and the development of myelin sheath in vivo. We propose a model in which cAMP signaling shuttles class IIa HDACs into the nucleus of Schwann cells to regulate the initial steps of myelination in the peripheral nervous system.


Asunto(s)
AMP Cíclico/metabolismo , Histona Desacetilasas/metabolismo , Vaina de Mielina/metabolismo , Fibras Nerviosas Mielínicas/enzimología , Células de Schwann/enzimología , Nervio Ciático/enzimología , Transcripción Genética , Transporte Activo de Núcleo Celular , Animales , Sitios de Unión , Células Cultivadas , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Histona Desacetilasas/deficiencia , Histona Desacetilasas/genética , Factores de Transcripción MEF2/genética , Factores de Transcripción MEF2/metabolismo , Ratones Noqueados , Vaina de Mielina/genética , Fibras Nerviosas Mielínicas/ultraestructura , Co-Represor 1 de Receptor Nuclear/genética , Co-Represor 1 de Receptor Nuclear/metabolismo , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratas Wistar , Células de Schwann/ultraestructura , Nervio Ciático/ultraestructura , Sistemas de Mensajero Secundario , Técnicas de Cultivo de Tejidos
18.
Cell Rep ; 20(11): 2719-2734, 2017 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-28903050

RESUMEN

Repair Schwann cells play a critical role in orchestrating nerve repair after injury, but the cellular and molecular processes that generate them are poorly understood. Here, we perform a combined whole-genome, coding and non-coding RNA and CpG methylation study following nerve injury. We show that genes involved in the epithelial-mesenchymal transition are enriched in repair cells, and we identify several long non-coding RNAs in Schwann cells. We demonstrate that the AP-1 transcription factor C-JUN regulates the expression of certain micro RNAs in repair Schwann cells, in particular miR-21 and miR-34. Surprisingly, unlike during development, changes in CpG methylation are limited in injury, restricted to specific locations, such as enhancer regions of Schwann cell-specific genes (e.g., Nedd4l), and close to local enrichment of AP-1 motifs. These genetic and epigenomic changes broaden our mechanistic understanding of the formation of repair Schwann cell during peripheral nervous system tissue repair.


Asunto(s)
Metilación de ADN/genética , Regeneración Nerviosa/genética , Traumatismos de los Nervios Periféricos/genética , ARN Largo no Codificante/genética , Células de Schwann/patología , Transcriptoma/genética , Animales , Islas de CpG/genética , Elementos de Facilitación Genéticos/genética , Transición Epitelial-Mesenquimal/genética , Regulación de la Expresión Génica , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Traumatismos de los Nervios Periféricos/patología , Fenotipo , ARN Largo no Codificante/metabolismo , Análisis de Secuencia de ARN , Factor de Transcripción AP-1/metabolismo
19.
J Cell Biol ; 210(1): 153-68, 2015 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-26150392

RESUMEN

Although Schwann cell myelin breakdown is the universal outcome of a remarkably wide range of conditions that cause disease or injury to peripheral nerves, the cellular and molecular mechanisms that make Schwann cell-mediated myelin digestion possible have not been established. We report that Schwann cells degrade myelin after injury by a novel form of selective autophagy, myelinophagy. Autophagy was up-regulated by myelinating Schwann cells after nerve injury, myelin debris was present in autophagosomes, and pharmacological and genetic inhibition of autophagy impaired myelin clearance. Myelinophagy was positively regulated by the Schwann cell JNK/c-Jun pathway, a central regulator of the Schwann cell reprogramming induced by nerve injury. We also present evidence that myelinophagy is defective in the injured central nervous system. These results reveal an important role for inductive autophagy during Wallerian degeneration, and point to potential mechanistic targets for accelerating myelin clearance and improving demyelinating disease.


Asunto(s)
Autofagia , Vaina de Mielina/patología , Traumatismos de los Nervios Periféricos/patología , Animales , Células Cultivadas , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Metabolismo de los Lípidos , Ratones Transgénicos , Vaina de Mielina/fisiología , Traumatismos de los Nervios Periféricos/enzimología , Proteínas Proto-Oncogénicas c-jun/metabolismo , Nervio Ciático/patología , Serina-Treonina Quinasas TOR/metabolismo , Degeneración Walleriana/patología
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