Constitutional mislocalization of Pten drives precocious maturation in oligodendrocytes and aberrant myelination in model of autism spectrum disorder.
Transl Psychiatry
; 9(1): 13, 2019 01 17.
Article
en En
| MEDLINE
| ID: mdl-30664625
ABSTRACT
There is a strong genetic association between germline PTEN mutation and autism spectrum disorder (ASD), making Pten-mutant models exemplary for the study of ASD pathophysiology. We developed the Ptenm3m4 mouse, where Pten is largely restricted from the nucleus, which recapitulates patient-like, autism-related phenotypes behavioral changes, macrocephaly, and white matter abnormalities. This study aimed to investigate the contribution of oligodendrocyte (OL) lineage differentiation and functional changes in myelination to the white matter phenotype. OL lineage differentiation and myelination in Ptenm3m4 mice was studied using immunohistochemical and electron microscopic analyses. We also used primary oligodendrocyte progenitor cells (OPCs) to determine the effect of the Ptenm3m4 mutation on OPC proliferation, migration and maturation. Finally, we assessed the myelinating competency of mutant OLs via co-culture with wildtype dorsal root ganglia (DRG) neurons. The in vivo analyses of Ptenm3m4/m3m4 murine brains showed deficits in proteolipid protein (Plp) trafficking in myelinating OLs. Despite the increased expression of myelin proteins in the brain, myelin deposition was observed to be abnormal, often occurring adjacent to, rather than around axons. Mutant primary OPCs showed enhanced proliferation and migration. Furthermore, mutant OPCs matured precociously, exhibiting aberrant myelination in vitro. Mutant OPCs, when co-cultured with wildtype DRG neurons, showed an inability to properly ensheath axons. Our findings provide evidence that the Ptenm3m4 mutation disrupts the differentiation and myelination programs of developing OLs. OL dysfunction in the Ptenm3m4 model explains the leukodystrophy phenotype, a feature commonly associated with autism, and highlights the growing importance of glial dysfunction in autism pathogenesis.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Encéfalo
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Neuroglía
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Fosfohidrolasa PTEN
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Trastorno del Espectro Autista
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Transl Psychiatry
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos