Dynamic Gene Expression in the Human Cerebral Cortex Distinguishes Children from Adults

In comparison with other primate species, humans have an extended juvenile period during which the brain is more plastic. In the current study we sought to examine gene expression in the cerebral cortex during development in the context of this adaptive plasticity. We introduce an approach designed to discriminate genes with variable as opposed to uniform patterns of gene expression and found that greater inter-individual variance is observed among children than among adults. For the 337 transcripts that show this pattern, we found a significant overrepresentation of genes annotated to the immune system process (pFDR≅0). Moreover, genes known to be important in neuronal function, such as brain-derived neurotrophic factor (BDNF), are included among the genes more variably expressed in childhood. We propose that the developmental period of heightened childhood neuronal plasticity is characterized by more dynamic patterns of gene expression in the cerebral cortex compared to adulthood when the brain is less plastic. That an overabundance of these genes are annotated to the immune system suggests that the functions of these genes can be thought of not only in the context of antigen processing and presentation, but also in the context of nervous system development

Dataset S4

Worksheet A. GOTerm and Gene List enrichment analyses by expression level, association with age and profile types. Worksheet B. GOTerm and Gene Lists information

Dataset S2

Association tests between age and medication/neuropathology variables

Data from: Characterization of human cortical gene expression in relation to glucose utilization.

Objectives: Human brain development follows a unique pattern characterized by a prolonged period of postnatal growth and reorganization, and a postnatal peak in glucose utilization. The molecular processes underlying these developmental changes are poorly characterized. The objectives of this study were to determine developmental trajectories of gene expression and to examine the evolutionary history of genes differentially expressed as a function of age. Methods: We used microarrays to determine age-related patterns of mRNA expression in human cerebral cortical samples ranging from infancy to adulthood. In contrast to previous developmental gene expression studies of human neocortex that relied on postmortem tissue, we measured mRNA expression from the nondiseased margins of surgically resected tissue. We used regression models designed to identify transcripts that followed significant linear or curvilinear functions of age and used population genetics techniques to examine the evolution of these genes. Results: We identified 40 transcripts with significant age-related trajectories in expression. Ten genes have documented roles in nervous system development and energy metabolism, others are novel candidates in brain development. Sixteen transcripts showed similar patterns of expression, characterized by decreasing expression during childhood. Comparative genomic analyses revealed that the regulatory regions of three genes have evidence of adaptive evolution in recent human evolution. Conclusions: These findings provide evidence that a subset of genes expressed in the human cerebral cortex broadly mirror developmental patterns of cortical glucose consumption. Whether there is a causal relationship between gene expression and glucose utilization remains to be determined

Dataset S5

Intersection of 36 genes differentially expressed in the cerebral cortex with Mammalian Genome Informatics Mammalian Phenotype data

Dataset S1

Probes significantly associated with age

Dataset S3

GOTerm and Kegg Pathway analyses for probes differentially expressed by age

Gene Ontology and KEGG pathway analyses

<p>(<b>reference  =  all genes</b>)<b>.</b> Gene Ontology Biological Process (GO_BP) and KEGG pathway analyses for probes with greater variance in childhood than in adulthood using as reference all genes called present on the array. The <i>expected</i> number of genes is the number of genes predicted for this term by random chance. The <i>observed</i> number of genes is the number of genes actually present in our dataset for this term. For example, in this context we would expect by random chance to see 13 genes annotated to the GO_BP term ‘immune system process’ (GO:0002376). Instead, we observed 75 genes annotated to this term (pFDR  = 0). The steepness of the slope of each line reflects statistical significance with steeper lines having smaller pFDR values. Those categories with the greatest slope (pFDR  = ≤0.02) are labeled in this figure. All 339 GO_BP terms and 19 KEGG pathways that met our enrichment criterion of pFDR ≤0.1 can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037714#pone.0037714.s005" target="_blank">Dataset S2</a>. Additional GO (Molecular Process and Cellular Component) data and plots can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037714#pone.0037714.s005" target="_blank">Dataset S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037714#pone.0037714.s001" target="_blank">Figure S1</a> respectively.</p

Immunohistochemistry evidence for expression of ‘immunity-related’ genes in neurons and glial cells.

<p>Immunohistochemistry showing the protein expression of C1Q, NP2 and HLA-E in nondiseased human glial cells and neurons. Arrows denote the location of microglia (M) and neurons (N). Images A–B show C1Q staining in frozen temporal lobe sections of two adults. Images C–D show C1Q staining of microglia and neurons, respectively, in frozen temporal lobe sections of a child. Image E shows NP2 staining of microglia and neurons in frozen temporal lobe sections of an adult. Image F is a negative control of the adult frozen temporal lobe tissue. Images G–H show NP2 staining of microglia and neurons, respectively, in paraffin embedded temporal lobe section of a child. Images I–J show HLA-E staining of both microglia and neurons in frozen temporal lobe sections of two adults. Image K shows HLA-E staining of microglia and neurons in a frozen temporal lobe section of a child. Image L is a negative control of the frozen temporal lobe section of the child. We found evidence for the expression of all three proteins in both cell types of the child. However, in the adult, NP2 and HLA-E were present in both cell types but there was no evidence of C1Q expression.</p