Gene expression abnormalities and oligodendrocyte deficits in the internal capsule in schizophrenia.
Deficits in the expression of oligodendrocyte (Ol) and myelin genes have been described in numerous brain regions in schizophrenia (SZ) in association with abnormalities of cell cycle markers. We have previously reported a SZ-associated decrease in the expression of genes expressed after, but not prior to, the terminal differentiation of Ols in the posterior limb of the internal capsule (ICp). This pattern of deficits could reflect a failure of Ol precursors to exit the cell cycle and differentiate to meet the demands imposed by the high rate of apoptosis among myelinating Ols. Here we explore this hypothesis using quantitative real time PCR to examine the mRNA expression of additional genes in the ICp of the previously examined sample of 14 subjects with SZ and 15 normal controls (NCs). The genes examined in the present study were chosen because they are associated with particular phases of the cell cycle (CCND1, CCND2, p21(Cip1), p27(Kip1), and p57(Kip2)), with DNA replication and repair (PCNA), apoptosis (CASP3), or the Notch signaling pathway (JAG1, HES1, HES5, andDTX1). The Notch pathway influences whether Ol precursors continue to proliferate or exit the cell cycle. We also determined the densities of Ols in the ICp. Genes associated with maintenance of the cell cycle tended to exhibit increased expression levels in SZ relative to NCs and to be negatively correlated with the expression levels of the previously assessed mature Ol genes. In contrast, genes associated with cell cycle arrest tended to show the opposite pattern (decreased expression in SZ and positive correlations with mature Ol genes). CASP3 and PCNA expression levels were significantly decreased in SZ and positively correlated with mature Ol genes, suggesting that myelinating Ols may turnover more rapidly in normal controls than in subjects with SZ. JAG1 expression was significantly increased in SZ and exhibited positive correlations with mediators of the canonical Notch pathway but negative correlations with mature Ol genes. Ol densities were significantly decreased in SZ. These data are consistent with the hypothesis that Ol and myelin deficits in SZ involve a failure of Ol precursors to appropriately exit the cell cycle in order to differentiate and mature into myelinating Ols.
Kerns
David
D
J.J. Peters VA Medical Center, 130 West Kingsbridge Ave., Bronx, New York, NY 10468, USA.
Vong
Ghe S
GS
Barley
Kevin
K
Dracheva
Stella
S
Katsel
Pavel
P
Casaccia
Patrizia
P
Haroutunian
Vahram
V
Byne
William
W
D000328:Adult; D000367:Age Factors; D000704:Analysis of Variance; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D056742:Cyclin D2 / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D020772:Internal Capsule / Q000473:pathology*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009836:Oligodendroglia / Q000473:pathology*; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000473:pathology*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000235:genetics*; D013223:Statistics as Topic; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D053148:Caspase 3; D019938:Cyclin D1; D056742:Cyclin D2; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C530104:CCND1 protein, human; C080336:CCND2 protein, human; C000606273:JAG1 protein, human; C078493:HES1 protein, human; C505407:CASP3 protein, human