Dataset Information

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.

SUBMITTER: Katsel P

PROVIDER: S-EPMC5890457 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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

Katsel Pavel P Fam Peter P Tan Weilun W Khan Sonia S Yang Chunxia C Jouroukhin Yan Y Rudchenko Sergei S Pletnikov Mikhail V MV Haroutunian Vahram V

Schizophrenia bulletin 20180401 3

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 hindbra ...[more]

PMID: 28981898

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Project description:Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. Quantitative real-time-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOEdev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.

Dataset Information

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

Publications

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

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