RESUMO
Protein Zero (P0), the major structural protein in the peripheral nervous system (PNS) myelin, acts as a homotypic adhesion molecule and is thought to mediate compaction of adjacent wraps of myelin membrane. E-Cadherin, a calcium-dependent adhesion molecule, is also expressed in myelinating Schwann cells in the PNS and is involved in forming adherens junctions between adjacent loops of membrane at the paranode. To determine the relationship, if any, between P0-mediated and cadherin-mediated adhesion during myelination, we investigated the expression of E-cadherin and its binding partner, beta-catenin, in sciatic nerve of mice lacking P0 (P0(-/-)). We find that in P0(-/-) peripheral myelin neither E-cadherin nor beta-catenin are localized to paranodes, but are instead found in small puncta throughout the Schwann cell. In addition, only occasional, often rudimentary, adherens junctions are formed. Analysis of E-cadherin and beta-catenin expression during nerve development demonstrates that E-cadherin and beta-catenin are localized to the paranodal region after the onset of myelin compaction. Interestingly, axoglial junction formation is normal in P0(-/-) nerve. Taken together, these data demonstrate that P0 is necessary for the formation of adherens junctions but not axoglial junctions in myelinating Schwann cells.
Assuntos
Junções Aderentes/metabolismo , Caderinas/metabolismo , Moléculas de Adesão Celular Neuronais , Proteínas do Citoesqueleto/metabolismo , Proteína P0 da Mielina/deficiência , Nervos Periféricos/crescimento & desenvolvimento , Nervos Periféricos/metabolismo , Células de Schwann/metabolismo , Transativadores , Junções Aderentes/ultraestrutura , Envelhecimento/genética , Animais , Axônios/metabolismo , Axônios/ultraestrutura , Caderinas/genética , Adesão Celular/genética , Comunicação Celular/genética , Proteínas do Citoesqueleto/genética , Imunofluorescência , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Proteína P0 da Mielina/genética , Bainha de Mielina/metabolismo , Bainha de Mielina/ultraestrutura , Glicoproteína Associada a Mielina/metabolismo , Compressão Nervosa , Nervos Periféricos/ultraestrutura , RNA Mensageiro/metabolismo , Nós Neurofibrosos/metabolismo , Nós Neurofibrosos/ultraestrutura , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular/metabolismo , Células de Schwann/ultraestrutura , Nervo Isquiático/crescimento & desenvolvimento , Nervo Isquiático/metabolismo , Nervo Isquiático/ultraestrutura , beta CateninaRESUMO
In order to better understand the pathogenesis of demyelination in P0 knockout (P0-/-) mice, we analyzed the myelin gene expression and the localization of myelin proteins in P0 null mouse sciatic nerve. We have demonstrated that the severe demyelinating neuropathy of P0-knockout mouse is associated with changes in the program of myelin gene expression. Some changes in myelin gene expression occur early, others occur during adulthood. We also provide evidence that the absence of P0 is associated with changes in the localization of specific paranodal proteins in the peripheral nerve. These data suggest that P0 plays an important role, either directly or indirectly, in the program of Schwann cell gene expression and in the specific distribution of peripheral myelin proteins. Furthermore, myelin gene dysregulation and improper localization of paranodal proteins may account, in part, for the pathogenesis of demyelination in P0-knockout mice, as well as in human demyelinating peripheral neuropathy associated with mutations in the P0 gene.
