DISC1 (Disrupted-in-Schizophrenia-1) Regulates Differentiation of Oligodendrocytes.

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a
translocation, t(1;11) (q42.1;q14.3), that segregates with major
psychiatric disorders, including schizophrenia, recurrent major
depression and bipolar affective disorder, in a Scottish family. Here we
report that mammalian DISC1 endogenously expressed in oligodendroglial
lineage cells negatively regulates differentiation of oligodendrocyte
precursor cells into oligodendrocytes. DISC1 expression was detected in
oligodendrocytes of the mouse corpus callosum at P14 and P70. DISC1 mRNA
was expressed in primary cultured rat cortical oligodendrocyte
precursor cells and decreased when oligodendrocyte precursor cells were
induced to differentiate by PDGF deprivation. Immunocytochemical
analysis showed that overexpressed DISC1 was localized in the cell
bodies and processes of oligodendrocyte precursor cells and
oligodendrocytes. We show that expression of the myelin related markers,
CNPase and MBP, as well as the number of cells with a matured
oligodendrocyte morphology, were decreased following full length DISC1
overexpression. Conversely, both expression of CNPase and the number of
oligodendrocytes with a mature morphology were increased following
knockdown of endogenous DISC1 by RNA interference. Overexpression of a
truncated form of DISC1 also resulted in an increase in expression of
myelin related proteins and the number of mature oligodendrocytes,
potentially acting via a dominant negative mechanism. We also identified
involvement of Sox10 and Nkx2.2 in the DISC1 regulatory pathway of
oligodendrocyte differentiation, both well-known transcription factors
involved in the regulation of myelin genes.

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