Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars

Beneš, Francine M.; Lim, Benjamin; Subburaju, Sivan

doi:10.1073/pnas.0903066106

Cited by 53 publications

(44 citation statements)

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“…The DNA damage response in post-mitotic neurons includes cell-cycle arrest coupled with DNA repair, apoptosis, senescence and differentiation (Benes et al, 2009, Nguyen et al, 2002). However, the cell-cycle machinery, in general, and cell-cycle proteins active at the G1/S checkpoint may also contribute to terminal post-mitotic differentiation of neurons, early neuronal development, epigenetic regulation, signaling (ie., Wnt/β-catenin) and neuronal polarization (Lim and Kaldis, 2013).…”

Section: Discussionmentioning

confidence: 99%

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

Xiao

Vemula

Xue

et al. 2016

Experimental Neurology

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A missense mutation in CIZ1 (c.790A > G, p.S264G) was linked to autosomal dominant cervical dystonia in a large multiplex Caucasian pedigree (OMIM614860, DYT23). CIZ1 is a p21(Cip1/Waf1) -interacting zinc finger protein, widely expressed in neural and extra-neural tissues, and plays a role in DNA synthesis at the G1/S cell-cycle checkpoint. The role of CIZ1 in the nervous system and relative contributions of gain- or loss- of function to the pathogenesis of CIZ1-associated dystonia remain indefinite. Using relative quantitative reverse transcriptase-PCR, cerebellum showed the highest expression levels of Ciz1 in adult mouse brain, over two fold higher than liver, and higher than striatum, midbrain and cerebral cortex. Overall, neural expression of Ciz1 increased with postnatal age. A Ciz1 gene-trap knock-out (KO) mouse model (Ciz1−/−) was generated to examine the functional role(s) of CIZ1 in the sensorimotor nervous system and contributions of CIZ1 to cell-cycle control in the mammalian brain. Ciz1 transcripts were absent in Ciz1−/− mice and reduced by approximately 50% in Ciz1+/− mice. Ciz1−/− mice were fertile but smaller than wild-type (WT) littermates. Ciz1−/− mice did not manifest dystonia, but exhibited mild motoric abnormalities on balance, open-field activity, and gait. To determine the effects of germline KO of Ciz1 on whole-genome gene expression in adult brain, total RNA from mouse cerebellum was harvested from 6 10-month old Ciz1−/− mice and 6 age- and gender- matched WT littermates for whole-genome gene expression analysis. Based on whole-genome gene-expression analyses, genes involved in cellular movement, cell development, cellular growth, cellular morphology and cell-to-cell signaling and interaction were up-regulated in Ciz1−/− mice. The top up-regulated pathways were metabolic and cytokine-cytokine receptor interactions. Down-regulated genes were involved in cell cycle, cellular development, cell death and survival, gene expression and cell morphology. Down-regulated networks included those related to metabolism, focal adhesion, neuroactive ligand-receptor interaction, and MAPK signaling. Based on pathway analyses, transcription factor 7-like 2 (TCF7L2), a member of the Wnt/β-catenin signaling pathway, was a major hub for down-regulated genes, whereas NF-κB was a major hub for up-regulated genes. In aggregate, these data suggest that CIZ1 may be involved in the post-mitotic differentiation of neurons in response to external signals and changes in gene expression may compensate, in part, for CIZ1 deficiency in our Ciz1−/− mouse model. Although CIZ1 deficiency was associated with mild motor abnormalities, germline loss of Ciz1 was not associated with dystonia on the C57BL/6J background.

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Section: Discussionmentioning

confidence: 99%

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

Xiao

Vemula

Xue

et al. 2016

Experimental Neurology

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“…This inf luence may extend beyond cortical development. These genes continue to be expressed in adult forebrain neurons and precursors (11), and may be part of larger cell-cycle regulatory networks that are differentially disrupted in schizophrenic and bipolar patients (46). Last, altered cell-cycle control in cortical precursors due to diminished 22q11 gene dosage may also contribute to increased tumorigenesis in 22q11 patients (47).…”

Section: Discussionmentioning

confidence: 99%

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

Meechan¹,

Tucker²,

Maynard³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

155

173

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The 22q11 deletion (or DiGeorge) syndrome (22q11DS), the result of a 1.5-to 3-megabase hemizygous deletion on human chromosome 22, results in dramatically increased susceptibility for ''diseases of cortical connectivity'' thought to arise during development, including schizophrenia and autism. We show that diminished dosage of the genes deleted in the 1.5-megabase 22q11 minimal critical deleted region in a mouse model of 22q11DS specifically compromises neurogenesis and subsequent differentiation in the cerebral cortex. Proliferation of basal, but not apical, progenitors is disrupted, and subsequently, the frequency of layer 2/3, but not layer 5/6, projection neurons is altered. This change is paralleled by aberrant distribution of parvalbuminlabeled interneurons in upper and lower cortical layers. Deletion of Tbx1 or Prodh (22q11 genes independently associated with 22q11DS phenotypes) does not similarly disrupt basal progenitors. However, expression analysis implicates additional 22q11 genes that are selectively expressed in cortical precursors. Thus, diminished 22q11 gene dosage disrupts cortical neurogenesis and interneuron migration. Such developmental disruption may alter cortical circuitry and establish vulnerability for developmental disorders, including schizophrenia and autism. psychiatric disease T he neurodevelopmental hypothesis for diseases of cortical connectivity, initially proposed for schizophrenia (1), and later extended to autism spectrum disorders (2), suggests that anomalous cortical development underlies behavioral pathology. Despite inferred relationships between suspect developmental mechanisms, neuroanatomical or functional changes in patients, and postmortem cortical pathology, to our knowledge, there are no known direct links between specific cortical developmental mechanisms and pathogenesis. The near impossibility of prospective analyses in at-risk human fetuses further complicates rigorous evaluation of the hypothesis. Thus, the hypothesis may be more effectively evaluated in animal models of genetic or environmental risk for relevant diseases. In humans, 22q11 deletion/DiGeorge syndrome (22q11DS) confers the highest known genetic risk for schizophrenia (Ϸ30%) (3, 4), increased susceptibility for autism spectrum disorders (Ϸ25%) (5), and vulnerability for additional behavioral and learning disabilities (Ͼ60%) (5). Brain imaging in 22q11DS patients shows consistent anatomical defects, including reduced cortical gray matter and polymicrogyria (6-8), and postmortem analysis indicates cellular pathology associated with developmental defects including periventricular heteropias (9). We found that diminished 22q11 gene dosage in a 22q11DS mouse model compromises specific cortical neural stem cells, basal progenitors, and alters frequency and distribution of cortical projection neurons and GABAergic interneurons. These phenotypes suggest a link between a genomic lesion, altered cortical development, and subsequent changes in cortical circuitry that likely intensify risk for behavioral diso...

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“…Previous work has shown that a network of 28 genes is associated with the regulation of glutamic acid decarboxylase 67 (GAD67) in the hippocampus and that this network interacts with other gene networks in maintaining genome integrity in specific neurons (Benes et al, 2009). GAD67, a marker for GABAergic neurons, is downregulated in the cortex and hippocampus of SZ and BP+ patients (Akbarian and Huang, 2006;Volk et al, 2000;Guidotti et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

“…GAD67, a marker for GABAergic neurons, is downregulated in the cortex and hippocampus of SZ and BP+ patients (Akbarian and Huang, 2006;Volk et al, 2000;Guidotti et al, 2000). This gene cluster was uncovered during a network association analysis of cDNAs exhibiting compromised expression in CA3/2 hippocampal GABAergic neurons in SZ and BP disorder patients (Benes et al, 2009). The more recent study (Sheng et al, 2012) shows that there are highly significant changes in the magnitude and direction of individual gene copy number intensities in this GAD67 regulatory network.…”

Section: Introductionmentioning

confidence: 99%

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

Grayson

Guidotti

2012

Neuropsychopharmacol

244

214

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Major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BP) with psychosis (BP+ ) express a complex symptomatology characterized by positive symptoms, negative symptoms, and cognitive impairment. Postmortem studies of human SZ and BP+ brains show considerable alterations in the transcriptome of a variety of cortical structures, including multiple mRNAs that are downregulated in both inhibitory GABAergic and excitatory pyramidal neurons compared with non-psychiatric subjects (NPS). Several reports show increased expression of DNA methyltransferases in telencephalic GABAergic neurons. Accumulating evidence suggests a critical role for altered DNA methylation processes in the pathogenesis of SZ and related psychiatric disorders. The establishment and maintenance of CpG site methylation is essential during central nervous system differentiation and this methylation has been implicated in synaptic plasticity, learning, and memory. Atypical hypermethylation of candidate gene promoters expressed in GABAergic neurons is associated with transcriptional downregulation of the corresponding mRNAs, including glutamic acid decarboxylase 67 (GAD67) and reelin (RELN). Recent reports indicate that the methylation status of promoter proximal CpG dinucleotides is in a dynamic balance between DNA methylation and DNA hydroxymethylation. Hydroxymethylation and subsequent DNA demethylation is more complex and involves additional proteins downstream of 5-hydroxymethylcytosine, including members of the base excision repair (BER) pathway. Recent advances in our understanding of altered CpG methylation, hydroxymethylation, and active DNA demethylation provide a framework for the identification of new targets, which may be exploited for the pharmacological intervention of the psychosis associated with SZ and possibly BP+ .

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Site-specific regulation of cell cycle and DNA repair in post-mitotic GABA cells in schizophrenic versus bipolars

Cited by 53 publications

References 45 publications

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

Motor phenotypes and molecular networks associated with germline deficiency of Ciz1

Diminished dosage of 22q11 genes disrupts neurogenesis and cortical development in a mouse model of 22q11 deletion/DiGeorge syndrome

The Dynamics of DNA Methylation in Schizophrenia and Related Psychiatric Disorders

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