Overexpression of Truncated Human DISC1 Induces Appearance of Hindbrain Oligodendroglia in the Forebrain During Development.

Abstract

Genetic, neuroimaging, and gene expression studies suggest a role for oligodendrocyte (OLG) dysfunction in schizophrenia (SZ). Disrupted-in-schizophrenia 1 (DISC1) is a risk gene for major psychiatric disorders, including SZ. Overexpression of mutant truncated (hDISC1), but not full-length sequence of human DISC1 in forebrain influenced OLG differentiation and proliferation of glial progenitors in the developing cerebral cortex concurrently with reduction of OLG progenitor markers in the hindbrain. We examined gene and protein expression of the molecular determinants of hindbrain OLG development and their interactions with DISC1 in mutant hDISC1 mice. We found ectopic upregulation of hindbrain glial progenitor markers (early growth response 2 [Egr2] and NK2 homeobox 2 [Nkx2-2]) in the forebrain of hDISC1 (E15) embryos. DISC1 and Nkx2-2 were coexpressed and interacted in progenitor cells. Overexpression of truncated hDISC1 impaired interactions between DISC1 and Nkx2-2, which was associated with increased differentiation of OLG and upregulation of hindbrain mature OLG markers (laminin alpha-1 [LAMA1] and myelin protein zero [MPZ]) suggesting a suppressive function of endogenous DISC1 in OLG specialization of hindbrain glial progenitors during embryogenesis. Consistent with findings in hDISC1 mice, several hindbrain OLG markers (PRX, LAMA1, and MPZ) were significantly upregulated in the superior temporal cortex of persons with SZ. These findings show a significant effect of truncated hDISC1 on glial identity cells along the rostrocaudal axis and their OLG specification. Appearance of hindbrain OLG lineage cells and their premature differentiation may affect cerebrocortical organization and contribute to the pathophysiology of SZ.