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1.
Development ; 146(9)2019 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-31048318

RESUMEN

Myelination leads to the formation of myelin sheaths surrounding neuronal axons and is crucial for function, plasticity and repair of the central nervous system (CNS). It relies on the interaction of the axons and the oligodendrocytes: the glial cells producing CNS myelin. Here, we have investigated the role of a crucial component of the Sonic hedgehog (Shh) signalling pathway, the co-receptor Boc, in developmental and repairing myelination. During development, Boc mutant mice display a transient decrease in oligodendroglial cell density together with delayed myelination. Despite recovery of oligodendroglial cells at later stages, adult mutants still exhibit a lower production of myelin basic protein correlated with a significant decrease in the calibre of callosal axons and a reduced amount of the neurofilament NF-M. During myelin repair, the altered OPC differentiation observed in the mutant is reminiscent of the phenotype observed after blockade of Shh signalling. In addition, Boc mutant microglia/macrophages unexpectedly exhibit the apparent inability to transition from a highly to a faintly ramified morphology in vivo Altogether, these results identify Boc as an important component of myelin formation and repair.


Asunto(s)
Inmunoglobulina G/metabolismo , Vaina de Mielina/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Western Blotting , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Cuprizona/farmacología , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Inmunoglobulina G/genética , Filamentos Intermedios/efectos de los fármacos , Filamentos Intermedios/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/efectos de los fármacos , Microglía/metabolismo , Vaina de Mielina/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Oligodendroglía/metabolismo , Receptores de Superficie Celular/genética
2.
Glia ; 69(6): 1369-1392, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33484204

RESUMEN

Hedgehog morphogens control fundamental cellular processes during tissue development and regeneration. In the central nervous system (CNS), Hedgehog signaling has been implicated in oligodendrocyte and myelin production, where it functions in a concerted manner with other pathways. Since androgen receptor (AR) plays a key role in establishing the sexual phenotype of myelin during development and is required for spontaneous myelin regeneration in the adult CNS, we hypothesized the existence of a possible coordination between Hedgehog and androgen signals in oligodendrocyte and myelin production. Here, we report complementary activities of both pathways during early postnatal oligodendrogenesis further revealing that persistent Hedgehog signaling activation impedes myelin production. The data also uncover prominent pro-myelinating activity of testosterone and involvement of AR in the control of neural stem cell commitment toward the oligodendroglial lineage. In the context of CNS demyelination, we provide evidence for the functional cooperation of the pathways leading to acceleration of myelin regeneration that might be related to their respective role on microglial and astroglial responses, higher preservation of axonal integrity, lower neuroinflammation, and functional improvement of animals in an immune model of CNS demyelination. Strong decreases of deleterious cytokines in the CNS (GM-CSF, TNF-α, IL-17A) and spleen (IL-2, IFN-γ) stand as unique features of the combined drugs while the potent therapeutic activity of testosterone on peripheral immune cells contributes to increase tolerogenic CD11c+ dendritic cells, reduce the clonal expansion of conventional CD4+ T cells and increase CD4+ Foxp3+ regulatory T cells. Altogether, these data might open promising perspectives for demyelinating diseases.


Asunto(s)
Transducción de Señal , Andrógenos , Animales , Enfermedades Desmielinizantes , Proteínas Hedgehog , Vaina de Mielina , Enfermedades Neuroinflamatorias , Oligodendroglía , Testosterona
3.
FASEB J ; 34(10): 13641-13653, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32862444

RESUMEN

Leucine-rich repeat and immunoglobin-domain containing (LRRIG) proteins that are commonly involved in protein-protein interactions play important roles in nervous system development and maintenance. LINGO-1, one of this family members, is characterized as a negative regulator of neuronal survival, axonal regeneration, and oligodendrocyte precursor cell (OPC) differentiation into mature myelinating oligodendrocytes. Three LINGO-1 homologs named LINGO-2, LINGO-3, and LINGO-4 have been described. However, their relative expression and functions remain unexplored. Here, we show by in situ hybridization and quantitative polymerase chain reaction that the transcripts of LINGO homologs are differentially expressed in the central nervous system. The immunostaining of brain slices confirmed this observation and showed the co-expression of LINGO-1 with its homologs. Using BRET (bioluminescence resonance energy transfer) analysis, we demonstrate that LINGO proteins can physically interact with each of the other ones with comparable affinities and thus form the oligomeric states. Furthermore, co-immunoprecipitation experiments indicate that LINGO proteins form heterocomplexes in both heterologous systems and cortical neurons. Since LINGO-1 is a promising target for the treatment of demyelinating diseases, its ability to form heteromeric complexes reveals a new level of complexity in its functioning and opens the way for new strategies to achieve diverse and nuanced LINGO-1 regulation.


Asunto(s)
Encéfalo/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Multimerización de Proteína , Animales , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Ratones , Proteínas del Tejido Nervioso/genética , Unión Proteica
4.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-33810425

RESUMEN

Motor neurons and their axons reaching the skeletal muscle have long been considered as the best characterized targets of the degenerative process observed in amyotrophic lateral sclerosis (ALS). However, the involvement of glial cells was also more recently reported. Although oligodendrocytes have been underestimated for a longer time than other cells, they are presently considered as critically involved in axonal injury and also conversely constitute a target for the toxic effects of the degenerative neurons. In the present review, we highlight the recent advances regarding oligodendroglial cell involvement in the pathogenesis of ALS. First, we present the oligodendroglial cells, the process of myelination, and the tight relationship between axons and myelin. The histological abnormalities observed in ALS and animal models of the disease are described, including myelin defects and oligodendroglial accumulation of pathological protein aggregates. Then, we present data that establish the existence of dysfunctional and degenerating oligodendroglial cells, the chain of events resulting in oligodendrocyte degeneration, and the most recent molecular mechanisms supporting oligodendrocyte death and dysfunction. Finally, we review the arguments in support of the primary versus secondary involvement of oligodendrocytes in the disease and discuss the therapeutic perspectives related to oligodendrocyte implication in ALS pathogenesis.


Asunto(s)
Esclerosis Amiotrófica Lateral/metabolismo , Enfermedades Desmielinizantes/fisiopatología , Oligodendroglía/citología , Animales , Astrocitos/citología , Axones/metabolismo , Muerte Celular , Linaje de la Célula , Proliferación Celular , Proteínas de Unión al ADN/química , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Ratones , Neuronas Motoras/metabolismo , Vaina de Mielina/metabolismo , Neuroglía/metabolismo , Oxígeno/química , Prosencéfalo/metabolismo , Ratas , Médula Espinal/metabolismo , Superóxido Dismutasa-1/metabolismo
5.
Proc Natl Acad Sci U S A ; 113(51): 14829-14834, 2016 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-27930320

RESUMEN

Lost myelin can be replaced after injury or during demyelinating diseases in a regenerative process called remyelination. In the central nervous system (CNS), the myelin sheaths, which protect axons and allow the fast propagation of electrical impulses, are produced by oligodendrocytes. The abundance and widespread distribution of oligodendrocyte progenitors (OPs) within the adult CNS account for this remarkable regenerative potential. Here, we report a key role for the male gonad, testosterone, and androgen receptor (AR) in CNS remyelination. After lysolecithin-induced demyelination of the male mouse ventral spinal cord white matter, the recruitment of glial fibrillary acidic protein-expressing astrocytes was compromised in the absence of testes and testosterone signaling via AR. Concomitantly, the differentiation of OPs into oligodendrocytes forming myelin basic protein (MBP)+ and proteolipid protein-positive myelin was impaired. Instead, in the absence of astrocytes, axons were remyelinated by protein zero (P0)+ and peripheral myelin protein 22-kDa (PMP22)+ myelin, normally only produced by Schwann cells in the peripheral nervous system. Thus, testosterone favors astrocyte recruitment and spontaneous oligodendrocyte-mediated remyelination. This finding may have important implications for demyelinating diseases, psychiatric disorders, and cognitive aging. The testosterone dependency of CNS oligodendrocyte remyelination may have roots in the evolutionary history of the AR, because the receptor has evolved from an ancestral 3-ketosteroid receptor through gene duplication at the time when myelin appeared in jawed vertebrates.


Asunto(s)
Vaina de Mielina/metabolismo , Receptores Androgénicos/metabolismo , Remielinización , Andrógenos/metabolismo , Animales , Astrocitos/citología , Astrocitos/metabolismo , Sistema Nervioso Central/metabolismo , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Fluorescente , Neuroglía/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Receptores de Esteroides/metabolismo , Células de Schwann/metabolismo , Transducción de Señal , Testículo/metabolismo , Testosterona/metabolismo
6.
Circ Res ; 112(5): 762-70, 2013 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-23343527

RESUMEN

RATIONALE: Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. OBJECTIVE: The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. METHODS AND RESULTS: We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle. CONCLUSIONS: This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.


Asunto(s)
Proteínas Hedgehog/fisiología , Miembro Posterior/irrigación sanguínea , Isquemia/fisiopatología , Neovascularización Fisiológica/fisiología , Nervios Periféricos/fisiología , Angiopoyetina 1/metabolismo , Animales , Supervivencia Celular/fisiología , Modelos Animales de Enfermedad , Proteínas Hedgehog/deficiencia , Proteínas Hedgehog/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Desnervación Muscular , Músculo Esquelético/inervación , Factores de Crecimiento Nervioso/metabolismo , Nervios Periféricos/citología , Células de Schwann/citología , Células de Schwann/fisiología , Transducción de Señal/fisiología , Factor A de Crecimiento Endotelial Vascular/metabolismo
7.
J Neurosci ; 33(5): 1759-72, 2013 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-23365216

RESUMEN

The morphogen Sonic Hedgehog (Shh) controls the generation of oligodendrocyte (OLs) during embryonic development and regulates OL production in adulthood in the cortex and corpus callosum. The roles of Shh in CNS repair following lesions associated with demyelinating diseases are still unresolved. Here, we address this issue by using a model of focal demyelination induced by lysolecithin in the corpus callosum of adult mice. Shh transcripts and protein were not detected in control animals but were upregulated in a time-dependent manner in the oligodendroglial lineage within the lesion. We report an increased transcription of Shh target genes suggesting a broad reactivation of the Shh pathway. We show that the adenovirus-mediated transfer of Shh into the lesioned brain results in the attenuation of the lesion extent with the increase of OL progenitor cells (OPCs) and mature myelinating OL numbers due to survival, proliferation, and differentiation activities as well as the decrease of astrogliosis and macrophage infiltration. Furthermore, the blocking of Shh signaling during the lesion, using its physiological antagonist, Hedgehog interacting protein, results in a decrease of OPC proliferation and differentiation, preventing repair. Together, our findings identify Shh as a necessary factor playing a positive role during demyelination and indicate that its signaling activation stands as a potential therapeutic approach for myelin diseases.


Asunto(s)
Cuerpo Calloso/metabolismo , Enfermedades Desmielinizantes/metabolismo , Proteínas Hedgehog/metabolismo , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Animales , Cuerpo Calloso/patología , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/patología , Expresión Génica , Proteínas Hedgehog/genética , Ratones , Vaina de Mielina/patología , Oligodendroglía/patología , Transducción de Señal/genética , Transcripción Genética
8.
Arterioscler Thromb Vasc Biol ; 33(12): 2858-66, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24135022

RESUMEN

OBJECTIVE: The purpose of this study is to further document alteration of signal transduction pathways, more particularly of hedgehog (Hh) signaling, causing impaired ischemic muscle repair in old mice. APPROACH AND RESULTS: We used 12-week-old (young mice) and 20- to 24-month-old C57BL/6 mice (old mice) to investigate the activity of Hh signaling in the setting of hindlimb ischemia-induced angiogenesis and skeletal muscle repair. In this model, delayed ischemic muscle repair observed in old mice was associated with an impaired upregulation of Gli1. Sonic Hh expression was not different in old mice compared with young mice, whereas desert Hh (Dhh) expression was downregulated in the skeletal muscle of old mice both in healthy and ischemic conditions. The rescue of Dhh expression by gene therapy in old mice promoted ischemia-induced angiogenesis and increased nerve density; nevertheless, it failed to promote myogenesis or to increase Gli1 mRNA expression. After further investigation, we found that, in addition to Dhh, smoothened expression was significantly downregulated in old mice. We used smoothened haploinsufficient mice to demonstrate that smoothened knockdown by 50% is sufficient to impair activation of Hh signaling and ischemia-induced muscle repair. CONCLUSIONS: The present study demonstrates that Hh signaling is impaired in aged mice because of Dhh and smoothened downregulation. Moreover, it shows that hegdehog-dependent regulation of angiogenesis and myogenesis involves distinct mechanisms.


Asunto(s)
Envejecimiento/metabolismo , Proteínas Hedgehog/metabolismo , Isquemia/metabolismo , Desarrollo de Músculos , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Neovascularización Fisiológica , Factores de Edad , Envejecimiento/genética , Animales , Células COS , Chlorocebus aethiops , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Terapia Genética , Proteínas Hedgehog/genética , Miembro Posterior , Inmunoglobulina G/genética , Inmunoglobulina G/metabolismo , Isquemia/genética , Isquemia/patología , Isquemia/fisiopatología , Isquemia/terapia , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/inervación , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Regeneración , Transducción de Señal , Receptor Smoothened , Transfección , Proteína con Dedos de Zinc GLI1
9.
Differentiation ; 85(4-5): 182-9, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23827460

RESUMEN

The transgenic plp-GFP mouse line expressing the green fluorescent protein (GFP) driven by the mouse myelin proteolipid protein (plp) gene promoter has been previously used to study the contribution of the plp lineage to oligodendrocyte development in the embryonic brain. Here, we show that the GFP fluorescence reflects the developmental expression of proteolipid protein during the postnatal development until adulthood in brain slices and in primary cultures of plp-GFP(+) cells derived from postnatal animals. In the adult brain, plp-GFP-expressing cells are mature oligodendrocytes but not oligodendroglial progenitors. In the model of focal demyelination induced by lysolecithin (LPC) in the corpus callosum of adult plp-GFP animals, we observed an up-regulation of the morphogen Sonic Hedgehog (Shh) in the LPC-induced lesion but not in the control animals. Moreover, we show that the adenovirus-mediated transfer of Shh in the lesion results in the attenuation of the demyelination extent as evidenced by GFP fluorescence analysis in Shh-treated and control animals. Altogether these data show how plp-GFP fluorescence can be monitored to follow the oligodendrocyte lineage during demyelination and identify Shh morphogen as an important factor during repair.


Asunto(s)
Enfermedades Desmielinizantes/genética , Proteína Proteolipídica de la Mielina/metabolismo , Vaina de Mielina/patología , Oligodendroglía/metabolismo , Regiones Promotoras Genéticas/fisiología , Animales , Diferenciación Celular/fisiología , Linaje de la Célula , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Ratones , Ratones Transgénicos , Oligodendroglía/citología , Oligodendroglía/patología , Regulación hacia Arriba
10.
Cells ; 13(8)2024 Apr 13.
Artículo en Inglés | MEDLINE | ID: mdl-38667291

RESUMEN

Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females. Here, we developed an intranasal formulation containing the Hedgehog signaling agonist SAG, either alone or in combination with testosterone. We show that SAG promotes myelin regeneration and presumably a pro-regenerative phenotype of microglia, thus mimicking the effects previously observed in males. However, unlike in males, the combined molecules failed to cooperate in the demyelinated females, as shown by the level of functional improvement observed. Consistent with this observation, SAG administered in the absence of testosterone amplified peripheral inflammation by presumably activating NK cells and thus counteracting a testosterone-induced reduction in Th17 cells when the molecules were combined. Altogether, the data uncover a sex-dependent effect of the Hedgehog signaling agonist SAG on the peripheral innate immune system that conditions its ability to cooperate or not with androgens in the context of demyelination.


Asunto(s)
Enfermedades Desmielinizantes , Testosterona , Animales , Femenino , Masculino , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/tratamiento farmacológico , Ratones , Testosterona/farmacología , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/agonistas , Ratones Endogámicos C57BL , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Sistema Nervioso Central/metabolismo , Receptor Smoothened/metabolismo , Receptor Smoothened/agonistas , Vaina de Mielina/metabolismo , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Caracteres Sexuales
11.
Mol Pharmacol ; 83(5): 1020-9, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23448715

RESUMEN

Activation of the Smoothened (Smo) receptor mediates Hedgehog (Hh) signaling. Hh inhibitors are in clinical trials for cancer, and small-molecule Smo agonists may have therapeutic interests in regenerative medicine. Here, we have generated and validated a pharmacophoric model for Smo agonists and used this model for the virtual screening of a library of commercially available compounds. Among the 20 top-scoring ligands, we have identified and characterized a novel quinolinecarboxamide derivative, propyl 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido) benzoate, (GSA-10), as a Smo agonist. GSA-10 fits to the agonist pharmacophoric model with two hydrogen bond acceptor groups and four hydrophobic regions. Using pharmacological, biochemical, and molecular approaches, we provide compelling evidence that GSA-10 acts at Smo to promote the differentiation of multipotent mesenchymal progenitor cells into osteoblasts. However, this molecule does not display the hallmarks of reference Smo agonists. Remarkably, GSA-10 does not recognize the classic bodipy-cyclopamine binding site. Its effect on cell differentiation is inhibited by Smo antagonists, such as MRT-83, SANT-1, LDE225, and M25 in the nanomolar range, by GDC-0449 in the micromolar range, but not by cyclopamine and CUR61414. Thus, GSA-10 allows the pharmacological characterization of a novel Smo active site, which is notably not targeted to the primary cilium and strongly potentiated by forskolin and cholera toxin. GSA-10 belongs to a new class of Smo agonists and will be helpful for dissecting Hh mechanism of action, with important implications in physiology and in therapy.


Asunto(s)
Quinolinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Benzoatos/farmacología , Sitios de Unión/efectos de los fármacos , Receptores de Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/efectos de los fármacos , Línea Celular , AMP Cíclico/metabolismo , Ciclohexilaminas/farmacología , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Ligandos , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas , Receptor Smoothened , Tiofenos/farmacología , Factores de Transcripción/metabolismo , Proteínas Wnt/metabolismo , Proteína con Dedos de Zinc GLI1
12.
Arthritis Rheum ; 64(8): 2724-33, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22354771

RESUMEN

OBJECTIVE: Hedgehog signaling not only plays crucial roles during human development but also has been implicated in the pathogenesis of several diseases in adults. The aim of the present study was to investigate the role of the hedgehog pathway in fibroblast activation in systemic sclerosis (SSc). METHODS: Activation of the hedgehog pathway was analyzed by immunohistochemistry and real-time polymerase chain reaction (PCR). The effects of sonic hedgehog (SHH) on collagen synthesis were analyzed by reporter assays, real-time PCR, and Sircol assays. Myofibroblast differentiation was assessed by quantification of α-smooth muscle actin and stress fiber staining. The role of hedgehog signaling in vivo was analyzed by adenoviral overexpression of SHH and using mice lacking 1 allele of the gene for inhibitory receptor Patched homolog 1 (Ptch(+/-) mice). RESULTS: SHH was overexpressed and resulted in activation of hedgehog signaling in patients with SSc, with accumulation of the transcription factors Gli-1 and Gli-2 and increased transcription of hedgehog target genes. Activation of hedgehog signaling induced an activated phenotype in cultured fibroblasts, with differentiation of resting fibroblasts into myofibroblasts and increased release of collagen. Adenoviral overexpression of SHH in the skin of mice was sufficient to induce skin fibrosis. Moreover, Ptch(+/-) mice with increased hedgehog signaling were more sensitive to bleomycin-induced dermal fibrosis. CONCLUSION: We demonstrated that the hedgehog pathway is activated in patients with SSc. Hedgehog signaling potently stimulates the release of collagen and myofibroblast differentiation in vitro and is sufficient to induce fibrosis in vivo. These findings identify the hedgehog cascade as a profibrotic pathway in SSc.


Asunto(s)
Diferenciación Celular/fisiología , Fibroblastos/metabolismo , Proteínas Hedgehog/metabolismo , Esclerodermia Sistémica/metabolismo , Transducción de Señal/fisiología , Piel/metabolismo , Adulto , Anciano , Animales , Bleomicina/efectos adversos , Estudios de Casos y Controles , Células Cultivadas , Colágeno/metabolismo , Femenino , Fibroblastos/patología , Fibrosis/inducido químicamente , Humanos , Masculino , Ratones , Ratones Mutantes , Persona de Mediana Edad , Modelos Animales , Proteínas Oncogénicas/metabolismo , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular/genética , Esclerodermia Sistémica/patología , Piel/patología , Transactivadores/metabolismo , Vía de Señalización Wnt/fisiología , Proteína con Dedos de Zinc GLI1
13.
Differentiation ; 83(2): S97-104, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22169886

RESUMEN

The primary cilium has recently emerged as an important center for transduction of the Sonic Hedgehog (Shh) signal. Genetic studies have shown that Shh signaling at the level of primary cilia is essential for patterning the ventral neural tube and regulating adult stem cells. Some defects observed in human diseases and resulting from mutations affecting the organization of the primary cilium have been attributed to defective Shh signaling. The recent development of Shh pathway inhibitors for treating tumors linked to perturbations of Shh signaling has fostered studies to understand their mechanism of action in Shh receptor complex trafficking at the primary cilium.


Asunto(s)
Encéfalo/fisiología , Cilios/fisiología , Proteínas Hedgehog/metabolismo , Animales , Encéfalo/crecimiento & desarrollo , Trastornos de la Motilidad Ciliar/genética , Trastornos de la Motilidad Ciliar/metabolismo , Humanos , Transporte de Proteínas , Transducción de Señal
14.
Nat Commun ; 14(1): 1592, 2023 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-36949062

RESUMEN

Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.


Asunto(s)
Andrógenos , Esclerosis Múltiple , Animales , Ratones , Femenino , Masculino , Modelos Animales de Enfermedad , Vaina de Mielina/fisiología , Esclerosis Múltiple/genética , Esclerosis Múltiple/patología , Neuronas/patología
15.
Mol Pharmacol ; 79(3): 453-60, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21177415

RESUMEN

There is a clear need to develop novel pharmacological tools to improve our understanding of Smoothened (Smo) function in normal and pathological states. Here, we report the discovery, the mechanism of action, and the in vivo activity of N-(2-methyl-5-(3-(3,4,5-trimethoxybenzoyl)guanidino)phenyl)biphenyl-4-carboxamide (MRT-83), a novel potent antagonist of Smo that belongs to the acylguanidine family of molecules. MRT-83 fits to a proposed pharmacophoric model for Smo antagonists with three hydrogen bond acceptor groups and three hydrophobic regions. MRT-83 blocks Hedgehog (Hh) signaling in various assays with an IC50 in the nanomolar range, showing greater potency than the reference Smo antagonist cyclopamine. MRT-83 inhibits Bodipy-cyclopamine binding to human and mouse Smo but does not modify Wnt signaling in human embryonic kidney 293 transiently transfected with a Tcf/Lef-dependent Firefly luciferase reporter together with a Renilla reniformis luciferase control reporter. MRT-83 abrogates the agonist-induced trafficking of endogenous mouse or human Smo to the primary cilium of C3H10T1/2 or NT2 cells that derive from a pluripotent testicular carcinoma. Stereotaxic injection into the lateral ventricle of adult mice of MRT-83 but not of a structurally related compound inactive at Smo abolished up-regulation of Patched transcription induced by Sonic Hedgehog in the neighboring subventricular zone. These data demonstrate that MRT-83 efficiently antagonizes Hh signaling in vivo. All together, these molecular, functional and biochemical studies provide evidence that MRT-83 interacts with Smo. Thus, this novel Smo antagonist will be useful for manipulating Hh signaling and may help develop new therapies against Hh-pathway related diseases.


Asunto(s)
Benzamidas/farmacología , Guanidinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Línea Celular , Cerebelo/citología , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , Relación Dosis-Respuesta a Droga , Expresión Génica/efectos de los fármacos , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Ratones , Receptores Patched , Unión Proteica , Receptores de Superficie Celular/antagonistas & inhibidores , Receptores de Superficie Celular/biosíntesis , Receptores Acoplados a Proteínas G/biosíntesis , Transducción de Señal/efectos de los fármacos , Receptor Smoothened , Alcaloides de Veratrum/farmacología , Proteínas Wnt/efectos de los fármacos , Proteínas Wnt/fisiología
16.
Med Sci (Paris) ; 27(11): 979-85, 2011 Nov.
Artículo en Francés | MEDLINE | ID: mdl-22130025

RESUMEN

The identification of a Sonic Hedgehog (Shh) signaling pathway in the adult vertebrate central nervous system has paved the way to the characterization of the functional roles of Shh signals in normal and diseased brain. This morphogen is proposed to play a key role in the establishment and maintenance of adult neurogenic niches and to modulate the proliferation of neuronal or glial precursors. Consistent with its role during embryogenesis, alteration of Shh signaling is associated with tumorigenesis while its recruitment in damaged neural tissue might be part of the regenerating process. We will discuss the most recent data of the Hedgehog pathway in the adult brain and its relevance as a novel therapeutic approach for brain diseases including brain tumors.


Asunto(s)
Encefalopatías/etiología , Encéfalo/metabolismo , Proteínas Hedgehog/fisiología , Adulto , Animales , Encéfalo/embriología , Encefalopatías/genética , Encefalopatías/metabolismo , Encefalopatías/terapia , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Modelos Biológicos , Morfogénesis/genética , Neuronas/metabolismo , Neuronas/fisiología , Transducción de Señal/genética
17.
Front Cell Neurosci ; 15: 801704, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35082605

RESUMEN

The regeneration of myelin is known to restore axonal conduction velocity after a demyelinating event. Remyelination failure in the central nervous system contributes to the severity and progression of demyelinating diseases such as multiple sclerosis. Remyelination is controlled by many signaling pathways, such as the Sonic hedgehog (Shh) pathway, as shown by the canonical activation of its key effector Smoothened (Smo), which increases the proliferation of oligodendrocyte precursor cells via the upregulation of the transcription factor Gli1. On the other hand, the inhibition of Gli1 was also found to promote the recruitment of a subset of adult neural stem cells and their subsequent differentiation into oligodendrocytes. Since Smo is also able to transduce Shh signals via various non-canonical pathways such as the blockade of Gli1, we addressed the potential of non-canonical Smo signaling to contribute to oligodendroglial cell maturation in myelinating cells using the non-canonical Smo agonist GSA-10, which downregulates Gli1. Using the Oli-neuM cell line, we show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMP-activated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. Moreover, GSA-10 promotes the recruitment and differentiation of oligodendroglial progenitors into the demyelinated corpus callosum in vivo. Altogether, our data indicate that non-canonical signaling involving Smo/AMPK modulation and Gli1 downregulation promotes oligodendroglia maturation until axon engagement. Thus, GSA-10, by activation of this signaling pathway, represents a novel potential remyelinating agent.

18.
Mol Pharmacol ; 78(4): 658-65, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20664000

RESUMEN

The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated and validated a pharmacophoric model for Smo inhibitors constituted by three hydrogen bond acceptor groups and three hydrophobic regions. We used this model for the virtual screening of a library of commercially available compounds. Visual and structural criteria allowed the selection of 20 top scoring ligands, and an acylthiourea, N-(3-benzamidophenylcarbamothioyl)-3,4,5-trimethoxybenzamide (MRT-10), was identified and characterized as a Smo antagonist. The corresponding acylurea, N-(3-benzamidophenylcarbamoyl)-3,4,5-trimethoxybenzamide (MRT-14), was synthesized and shown to display, in various Hh assays, an inhibitory potency comparable to or greater than that of reference Smo antagonists cyclopamine and N-((3S,5S)-1-(benzo[d][1,3]dioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl)-N-(3-methoxybenzyl)-3,3-dimethylbutanamide (Cur61414). Focused virtual screening of the same library further identified five additional related antagonists. MRT-10 and MRT-14 constitute the first members of novel families of Smo antagonists. The described virtual screening approach is aimed at identifying novel modulators of Smo and of other G-protein coupled receptors.


Asunto(s)
Descubrimiento de Drogas/métodos , Bibliotecas Digitales , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Tiourea/química , Animales , Línea Celular , Evaluación Preclínica de Medicamentos/métodos , Humanos , Ratones , Ratones Endogámicos C3H , Receptores Acoplados a Proteínas G/fisiología , Receptor Smoothened , Tiourea/metabolismo
19.
J Neurochem ; 113(3): 576-90, 2010 May.
Artículo en Inglés | MEDLINE | ID: mdl-20218977

RESUMEN

The discovery of a Sonic Hedgehog (Shh) signaling pathway in the mature vertebrate CNS has paved the way to the characterization of the functional roles of Shh signals in normal and diseased brain. Shh is proposed to participate in the establishment and maintenance of adult neurogenic niches and to regulate the proliferation of neuronal or glial precursors in several brain areas. Consistent with its role during brain development, misregulation of Shh signaling is associated with tumorigenesis while its recruitement in damaged neural tissue might be part of the regenerating process. This review focuses on the most recent data of the Hedgehog pathway in the adult brain and its relevance as a novel therapeutic approach for brain diseases including brain tumors.


Asunto(s)
Encéfalo/fisiología , Proteínas Hedgehog/fisiología , Mamíferos/fisiología , Transducción de Señal/fisiología , Animales , Encefalopatías/fisiopatología , Neoplasias Encefálicas/fisiopatología , Diferenciación Celular/fisiología , Cilios/fisiología , Enfermedades Desmielinizantes/fisiopatología , Electrofisiología , Proteínas Hedgehog/biosíntesis , Proteínas Hedgehog/metabolismo , Humanos , Trastornos Mentales/fisiopatología , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Neuronas/metabolismo , Neurotransmisores/fisiología , Células Madre/fisiología
20.
Front Cell Neurosci ; 14: 79, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32317939

RESUMEN

Myelination is an essential process that consists of the ensheathment of axons by myelin. In the central nervous system (CNS), myelin is synthesized by oligodendrocytes. The proliferation, migration, and differentiation of oligodendrocyte precursor cells constitute a prerequisite before mature oligodendrocytes extend their processes around the axons and progressively generate a multilamellar lipidic sheath. Although myelination is predominately driven by oligodendrocytes, the other glial cells including astrocytes and microglia, also contribute to this process. The present review is an update of the most recent emerging mechanisms involving astrocyte and microglia in myelin production. The contribution of these cells will be first described during developmental myelination that occurs in the early postnatal period and is critical for the proper development of cognition and behavior. Then, we will report the novel findings regarding the beneficial or deleterious effects of astroglia and microglia, which respectively promote or impair the endogenous capacity of oligodendrocyte progenitor cells (OPCs) to induce spontaneous remyelination after myelin loss. Acute delineation of astrocyte and microglia activities and cross-talk should uncover the way towards novel therapeutic perspectives aimed at recovering proper myelination during development or at breaking down the barriers impeding the regeneration of the damaged myelin that occurs in CNS demyelinating diseases.

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