DNA arrays and neurobiology — what's new and what's next?

Barlow, Carrolee; Lockhart, David J.

doi:10.1016/s0959-4388(02)00353-7

Cited by 39 publications

(21 citation statements)

References 33 publications

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“…29,30 Our data reveal a robust differential signal that remains detectable despite cellular heterogeneity of PBMCs, and their apparent lack of primary involvement in the pathogenesis of PTSD. Of note, PBMCs are known to be perturbed following acute psychological stress, 18 in part through neuroendocrine and sympathetic modulation.…”

Section: Discussionmentioning

confidence: 73%

Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors

et al. 2005

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Trauma survivors show marked differences in the severity and persistence of post-traumatic stress disorder (PTSD) symptoms. Early symptoms subside in most, but persist as acute and chronic PTSD in a significant minority. The underlying molecular mechanisms or outcome predictors determining these differences are not known. Molecular markers for identifying any mental disorder are currently lacking. Gene expression profiling during the triggering and development of PTSD may be informative of its onset and course. We used oligonucleotide microarrays to measure peripheral blood mononuclear cell (PBMC) gene expression of trauma survivors at the emergency room and 4 months later. Gene expression signatures at both time points distinguished survivors who met DSM-IV diagnostic criteria for PTSD at 1 and 4 months, from those who met no PTSD criterion. Expression signatures at both time points correlated with the severity of each of the three PTSD symptom clusters assessed 4 months following exposure among all survivors. Results demonstrate a general reduction in PBMCs' expression of transcription activators among psychologically affected trauma survivors. Several differentiating genes were previously described as having a role in stress response. These findings provide initial evidence that peripheral gene expression signatures following trauma identify an evolving neuropsychiatric disorder and are informative of its key clinical features and outcome. Replications in larger samples, as well as studies focusing on specific markers within the signatures discovered, are warranted to confirm and extend the diagnostic utility and pathogenetic implications of our results. Molecular Psychiatry (2005) 10, 500-513.

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Section: Discussionmentioning

confidence: 73%

Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors

et al. 2005

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“…We and others have discussed the importance of methods to view data in three dimensions in the context of anatomy and͞or brain circuitry (5). As a step toward this goal, we have taken the observations of embryonic patterning and homeobox gene expression in the adult brain and combined the quantitative expression data with a high-resolution, coordinate-based brain atlas that allowed us to visualize the gene expression relationships in the context of the whole brain rather than simply as a list of genes.…”

Section: Resultsmentioning

confidence: 99%

“…Genome-wide gene expression profiling is a powerful technique for deriving information about specific brain regions (4,5). This approach has been used to measure gene expression patterns in particular regions, subregions, or cell populations in the brain (6)(7)(8)(9)(10)(11).…”

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confidence: 99%

“…However, the current study is the most extensive to date in terms of the number of genes and the coverage of different neural tissues. Our goal was to create a publicly accessible gene-based brain map with data sets, metadata, databases, and analysis tools available for use by the scientific community (5). As part of this work, we measured gene expression patterns for 24 neural tissues covering the adult mouse central nervous system plus 10 body regions.…”

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confidence: 99%

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Adult mouse brain gene expression patterns bear an embryologic imprint

Zapala

Hovatta²,

Ellison³

et al. 2005

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

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176

162

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The current model to explain the organization of the mammalian nervous system is based on studies of anatomy, embryology, and evolution. To further investigate the molecular organization of the adult mammalian brain, we have built a gene expression-based brain map. We measured gene expression patterns for 24 neural tissues covering the mouse central nervous system and found, surprisingly, that the adult brain bears a transcriptional ''imprint'' consistent with both embryological origins and classic evolutionary relationships. Embryonic cellular position along the anteriorposterior axis of the neural tube was shown to be closely associated with, and possibly a determinant of, the gene expression patterns in adult structures. We also observed a significant number of embryonic patterning and homeobox genes with region-specific expression in the adult nervous system. The relationships between global expression patterns for different anatomical regions and the nature of the observed region-specific genes suggest that the adult brain retains a degree of overall gene expression established during embryogenesis that is important for regional specificity and the functional relationships between regions in the adult. The complete collection of extensively annotated gene expression data along with data mining and visualization tools have been made available on a publicly accessible web site (www.barlow-lockhartbrainmapnimhgrant.org).database ͉ development ͉ evolution ͉ gene expression profiling ͉ inbred strains of mice T he adult nervous system achieves its mature form as the result of neuroectodermal cells committing to a specific fate and then segregating into distinct regional collectives of neurons that become fully functional through establishment of connections to other neurons. Our current understanding of brain architecture and organization is based on studies of embryology, anatomy, and evolution in which direct observation of anatomic structures was the foundation for postulated models of brain structure (1). Recent models of brain development and maturation consider relationships between different regions based on the expression of specific genes in assigning developmental origins of adult structures (2, 3). Here, we have constructed a regional gene expression atlas of the adult mouse brain and analyzed the quantitative results by using molecular classification algorithms.Genome-wide gene expression profiling is a powerful technique for deriving information about specific brain regions (4, 5). This approach has been used to measure gene expression patterns in particular regions, subregions, or cell populations in the brain (6-11). Two previous studies have analyzed gene expression differences across multiple regions of the mammalian brain by using multiple strains or species (12,13). However, the current study is the most extensive to date in terms of the number of genes and the coverage of different neural tissues. Our goal was to create a publicly accessible gene-based brain map with data sets, metadata, datab...

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“…We addressed the problems of high complexity and overlapping criteria by using a strategy combining powerful new gene microarray technology, which permits measurement of the expression of many thousands of genes simultaneously (36,37), with statistical correlation analyses. This strategy allowed the linking of gene expression to cognitive and pathological markers of AD independently of AD diagnosis.…”

mentioning

confidence: 99%

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

Blalock

Geddes

Chen

et al. 2004

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

938

853

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The pathogenesis of incipient Alzheimer's disease (AD) has been resistant to analysis because of the complexity of AD and the overlap of its early-stage markers with normal aging. Gene microarrays provide new tools for addressing complexity because they allow overviews of the simultaneous activity of multiple cellular pathways. However, microarray data interpretation is often hindered by low statistical power, high false positives or false negatives, and by uncertain relevance to functional endpoints. Here, we analyzed hippocampal gene expression of nine control and 22 AD subjects of varying severity on 31 separate microarrays. We then tested the correlation of each gene's expression with MiniMental Status Examination (MMSE) and neurofibrillary tangle (NFT) scores across all 31 subjects regardless of diagnosis. These well powered tests revealed a major transcriptional response comprising thousands of genes significantly correlated with AD markers. Several hundred of these genes were also correlated with AD markers across only control and incipient AD subjects (MMSE > 20). Biological process categories associated with incipient AD-correlated genes were identified statistically (EASE program) and revealed up-regulation of many transcription factor͞signaling genes regulating proliferation and differentiation, including tumor suppressors, oligodendrocyte growth factors, and protein kinase A modulators. In addition, up-regulation of adhesion, apoptosis, lipid metabolism, and initial inflammation processes occurred, and down-regulation of protein folding͞me-tabolism͞transport and some energy metabolism and signaling pathways took place. These findings suggest a new model of AD pathogenesis in which a genomically orchestrated up-regulation of tumor suppressor-mediated differentiation and involution processes induces the spread of pathology along myelinated axons. A lzheimer's disease (AD) has received intense study during past decades. Multiple processes have been implicated in AD, notably including abnormal ␤-amyloid (A␤) production (1-7), tau hyperphosphorylation and neurofibrillary tangles (NFTs) (8, 9), synaptic pathology (10-12), oxidative stress (13-15), inflammation (5, 16-19), protein processing or misfolding (20, 21), calcium dyshomeostasis (15,(20)(21)(22)(23)(24)(25)(26), aberrant reentry of neurons into the cell cycle (27, 28), cholesterol synthesis (29, 30), and effects of hormones (23, 31) or growth factors (17, 32). Nevertheless, the pathogenic factors that initiate these processes remain elusive.Several reasons account for the substantial resistance of AD pathogenesis to analysis. One is the vast extent and complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Another is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging, mild cognitive impairment, or incipient AD (33-35).We addressed the proble...

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DNA arrays and neurobiology — what's new and what's next?

Cited by 39 publications

References 33 publications

Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors

Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors

Adult mouse brain gene expression patterns bear an embryologic imprint

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

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