RESUMO
Slc17a5-/- mice represent an animal model for the infantile form of sialic acid storage disease (SASD). We analyzed genetic and histological time-course expression of myelin and oligodendrocyte (OL) lineage markers in different parts of the CNS, and related this to postnatal neurobehavioral development in these mice. Sialin-deficient mice display a distinct spatiotemporal pattern of sialic acid storage, CNS hypomyelination and leukoencephalopathy. Whereas few genes are differentially expressed in the perinatal stage (p0), microarray analysis revealed increased differential gene expression in later postnatal stages (p10-p18). This included progressive upregulation of neuroinflammatory genes, as well as continuous down-regulation of genes that encode myelin constituents and typical OL lineage markers. Age-related histopathological analysis indicates that initial myelination occurs normally in hindbrain regions, but progression to more frontal areas is affected in Slc17a5-/- mice. This course of progressive leukoencephalopathy and CNS hypomyelination delays neurobehavioral development in sialin-deficient mice. Slc17a5-/- mice successfully achieve early neurobehavioral milestones, but exhibit progressive delay of later-stage sensory and motor milestones. The present findings may contribute to further understanding of the processes of CNS myelination as well as help to develop therapeutic strategies for SASD and other myelination disorders.
Assuntos
Encéfalo/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Leucoencefalopatias , Transtornos Mentais/etiologia , Transportadores de Ânions Orgânicos/deficiência , Doença do Armazenamento de Ácido Siálico , Simportadores/deficiência , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/metabolismo , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/genética , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Filamentos Intermediários/metabolismo , Leucoencefalopatias/complicações , Leucoencefalopatias/etiologia , Leucoencefalopatias/genética , Proteína 1 de Membrana Associada ao Lisossomo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transportadores de Ânions Orgânicos/genética , Doença do Armazenamento de Ácido Siálico/complicações , Doença do Armazenamento de Ácido Siálico/genética , Doença do Armazenamento de Ácido Siálico/patologia , Simportadores/genéticaRESUMO
The migration of cells and the extension of cellular processes along pathways to their defined destinations are crucial in the development of higher organisms. Caenorhabditis elegans unc-53 plays an important role in cell migration and the outgrowth of cellular processes such as axons. To gain further insight into the biological function of unc53H2, a recently identified mammalian homologue of unc-53, we have generated mice carrying a mutation of unc53H2 and provide evidence that unc53H2 is involved in neuronal development and, more specifically, the development of different sensory systems. The unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation) which in case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve. We hypothesize that in analogy with its C. elegans homologue, unc53H2 may play a role in the processes of cellular outgrowth and migration.