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1.
Glia ; 66(5): 934-950, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29350423

RESUMO

During development of the central nervous system not all axons are myelinated, and axons may have distinct myelination patterns. Furthermore, the number of myelin sheaths formed by each oligodendrocyte is highly variable. However, our current knowledge about the axo-glia communication that regulates the formation of myelin sheaths spatially and temporally is limited. By using axon-mimicking microfibers and a zebrafish model system, we show that axonal ephrin-A1 inhibits myelination. Ephrin-A1 interacts with EphA4 to activate the ephexin1-RhoA-Rock-myosin 2 signaling cascade and causes inhibition of oligodendrocyte process extension. Both in myelinating co-cultures and in zebrafish larvae, activation of EphA4 decreases myelination, whereas myelination is increased by inhibition of EphA4 signaling at different levels of the pathway, or by receptor knockdown. Mechanistically, the enhanced myelination is a result of a higher number of myelin sheaths formed by each oligodendrocyte, not an increased number of mature cells. Thus, we have identified EphA4 and ephrin-A1 as novel negative regulators of myelination. Our data suggest that activation of an EphA4-RhoA pathway in oligodendrocytes by axonal ephrin-A1 inhibits stable axo-glia interaction required for generating a myelin sheath.


Assuntos
Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/metabolismo , Efrina-A1/metabolismo , Bainha de Mielina/metabolismo , Receptor EphA4/metabolismo , Animais , Animais Geneticamente Modificados , Axônios/metabolismo , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Técnicas de Cocultura , Ratos , Transdução de Sinais , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
2.
Sci Rep ; 14(1): 20161, 2024 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-39215168

RESUMO

Insulin-like growth factor (IGF) signaling is required for proper growth and skeletal development in vertebrates. Consequently, its dysregulation may lead to abnormalities of growth or skeletal structures. IGF is involved in the regulation of cell proliferation and differentiation of chondrocytes. However, the availability of bioactive IGF may be controlled by antagonizing IGF binding proteins (IGFBPs) in the circulation and tissues. As the metalloproteinase PAPP-A specifically cleaves members of the IGFBP family, we hypothesized that PAPP-A activity liberates bioactive IGF in cartilage. In PAPP-A knockout mice, the femur length was reduced and the mice showed a disorganized columnar organization of growth plate chondrocytes. Similarly, zebrafish lacking pappaa showed reduced length of Meckel's cartilage and disorganized chondrocytes, reminiscent of the mouse knockout phenotype. Expression of chondrocyte differentiation markers (sox9a, ihha, and col10a1) was markedly affected in Meckel's cartilage of pappaa knockout zebrafish, indicating that differentiation of chondrocytes was compromised. Additionally, the zebrafish pappaa knockout phenotype was mimicked by pharmacological inhibition of IGF signaling, and it could be rescued by treatment with exogenous recombinant IGF-I. In conclusion, our data suggests that IGF activity in the growing cartilage, and hence IGF signaling in chondrocytes, requires the presence of PAPP-A. The absence of PAPP-A causes aberrant chondrocyte organization and compromised growth in both mice and zebrafish.


Assuntos
Diferenciação Celular , Condrócitos , Proteína Plasmática A Associada à Gravidez , Peixe-Zebra , Animais , Camundongos , Cartilagem/metabolismo , Cartilagem/citologia , Condrócitos/metabolismo , Condrócitos/citologia , Condrogênese , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/citologia , Camundongos Knockout , Proteína Plasmática A Associada à Gravidez/metabolismo , Proteína Plasmática A Associada à Gravidez/genética , Transdução de Sinais , Somatomedinas/metabolismo , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
3.
Physiol Rep ; 11(15): e15793, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37568262

RESUMO

AIMS: Stanniocalcin-2 (STC2) has recently been implicated in human muscle mass variability by genetic analysis. Biochemically, STC2 inhibits the proteolytic activity of the metalloproteinase PAPP-A, which promotes muscle growth by upregulating the insulin-like growth factor (IGF) axis. The aim was to examine if STC2 affects skeletal muscle mass and to assess how the IGF axis mediates muscle hypertrophy induced by functional overload. METHODS: We compared muscle mass and muscle fiber morphology between Stc2-/- (n = 21) and wild-type (n = 15) mice. We then quantified IGF1, IGF2, IGF binding proteins -4 and -5 (IGFBP-4, IGFBP-5), PAPP-A and STC2 in plantaris muscles of wild-type mice subjected to 4-week unilateral overload (n = 14). RESULTS: Stc2-/- mice showed up to 10% larger muscle mass compared with wild-type mice. This increase was mediated by greater cross-sectional area of muscle fibers. Overload increased plantaris mass and components of the IGF axis, including quantities of IGF1 (by 2.41-fold, p = 0.0117), IGF2 (1.70-fold, p = 0.0461), IGFBP-4 (1.48-fold, p = 0.0268), PAPP-A (1.30-fold, p = 0.0154) and STC2 (1.28-fold, p = 0.019). CONCLUSION: Here we provide evidence that STC2 is an inhibitor of muscle growth upregulated, along with other components of the IGF axis, during overload-induced muscle hypertrophy.


Assuntos
Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina , Hormônios Peptídicos , Animais , Camundongos , Glicoproteínas/genética , Glicoproteínas/metabolismo , Hipertrofia , Proteína 4 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Músculo Esquelético/metabolismo , Hormônios Peptídicos/metabolismo , Proteína Plasmática A Associada à Gravidez/genética
4.
ASN Neuro ; 7(5)2015.
Artigo em Inglês | MEDLINE | ID: mdl-26354550

RESUMO

In the central nervous system, myelination of axons is required to ensure fast saltatory conduction and for survival of neurons. However, not all axons are myelinated, and the molecular mechanisms involved in guiding the oligodendrocyte processes toward the axons to be myelinated are not well understood. Only a few negative or positive guidance clues that are involved in regulating axo-glia interaction prior to myelination have been identified. One example is laminin, known to be required for early axo-glia interaction, which functions through α6ß1 integrin. Here, we identify the Eph-ephrin family of guidance receptors as novel regulators of the initial axo-glia interaction, preceding myelination. We demonstrate that so-called forward and reverse signaling, mediated by members of both Eph and ephrin subfamilies, has distinct and opposing effects on processes extension and myelin sheet formation. EphA forward signaling inhibits oligodendrocyte process extension and myelin sheet formation, and blocking of bidirectional signaling through this receptor enhances myelination. Similarly, EphB forward signaling also reduces myelin membrane formation, but in contrast to EphA forward signaling, this occurs in an integrin-dependent manner, which can be reversed by overexpression of a constitutive active ß1-integrin. Furthermore, ephrin-B reverse signaling induced by EphA4 or EphB1 enhances myelin sheet formation. Combined, this suggests that the Eph-ephrin receptors are important mediators of bidirectional signaling between axons and oligodendrocytes. It further implies that balancing Eph-ephrin forward and reverse signaling is important in the selection process of axons to be myelinated.


Assuntos
Axônios/fisiologia , Efrinas/metabolismo , Oligodendroglia/fisiologia , Receptores da Família Eph/metabolismo , Animais , Comunicação Celular/fisiologia , Diferenciação Celular/fisiologia , Células Cultivadas , Córtex Cerebral/fisiologia , Técnicas de Cocultura , Gânglios Espinais/crescimento & desenvolvimento , Gânglios Espinais/fisiologia , Integrinas/metabolismo , Bainha de Mielina/fisiologia , Células-Tronco Neurais/fisiologia , Ratos , Transdução de Sinais/fisiologia
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