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Transcriptional maturation of the mouse auditory forebrain.

Hackett TA, Guo Y, Clause A, Hackett NJ, Garbett K, Zhang P, Polley DB, Mirnics K - BMC Genomics (2015)

Bottom Line: Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age.Maturational changes are evident at the global through single gene levels.The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.

View Article: PubMed Central - PubMed

Affiliation: Department of Hearing and Speech Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA. troy.a.hackett@vanderbilt.edu.

ABSTRACT

Background: The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity increases markedly after the opening of the ear canals, initiating events that culminate in the maturation of auditory circuitry in the brain. This window provides a unique opportunity to study how gene expression patterns are modified by the onset of sensory experience through maturity. As a tool for capturing these features, next-generation sequencing of total RNA (RNAseq) has tremendous utility, because the entire transcriptome can be screened to index expression of any gene. To date, whole transcriptome profiles have not been generated for any central auditory structure in any species at any age. In the present study, RNAseq was used to profile two regions of the mouse auditory forebrain (A1, primary auditory cortex; MG, medial geniculate) at key stages of postnatal development (P7, P14, P21, adult) before and after the onset of hearing (~P12). Hierarchical clustering, differential expression, and functional geneset enrichment analyses (GSEA) were used to profile the expression patterns of all genes. Selected genesets related to neurotransmission, developmental plasticity, critical periods and brain structure were highlighted. An accessible repository of the entire dataset was also constructed that permits extraction and screening of all data from the global through single-gene levels. To our knowledge, this is the first whole transcriptome sequencing study of the forebrain of any mammalian sensory system. Although the data are most relevant for the auditory system, they are generally applicable to forebrain structures in the visual and somatosensory systems, as well.

Results: The main findings were: (1) Global gene expression patterns were tightly clustered by postnatal age and brain region; (2) comparing A1 and MG, the total numbers of differentially expressed genes were comparable from P7 to P21, then dropped to nearly half by adulthood; (3) comparing successive age groups, the greatest numbers of differentially expressed genes were found between P7 and P14 in both regions, followed by a steady decline in numbers with age; (4) maturational trajectories in expression levels varied at the single gene level (increasing, decreasing, static, other); (5) between regions, the profiles of single genes were often asymmetric; (6) GSEA revealed that genesets related to neural activity and plasticity were typically upregulated from P7 to adult, while those related to structure tended to be downregulated; (7) GSEA and pathways analysis of selected functional networks were not predictive of expression patterns in the auditory forebrain for all genes, reflecting regional specificity at the single gene level.

Conclusions: Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age. Maturational changes are evident at the global through single gene levels. Transcriptome profiles in A1 and MG are distinct at all ages, and differ from other brain regions. The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.

No MeSH data available.


Related in: MedlinePlus

Gene expression profiles of the synaptic vesicle exocytosis gene ontology category. Gene expression profiles are plotted for a subset of genes from one gene ontology category, selected from the GSEA analysis in Table 7 (GO: 0016079, synaptic vesicle exocytosis). For each gene, mean normalized counts and % of maximum counts are plotted by postnatal age (P7, P14, P21, Adult) and brain region (A1, MG). Expression trajectory is indicated by arrows (up, down, none). Arrows were included only when differential expression from P7-Adult was significant (p < 0.05) by all three methods (DEseq2, EdgeR, and Bayseq)
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Fig5: Gene expression profiles of the synaptic vesicle exocytosis gene ontology category. Gene expression profiles are plotted for a subset of genes from one gene ontology category, selected from the GSEA analysis in Table 7 (GO: 0016079, synaptic vesicle exocytosis). For each gene, mean normalized counts and % of maximum counts are plotted by postnatal age (P7, P14, P21, Adult) and brain region (A1, MG). Expression trajectory is indicated by arrows (up, down, none). Arrows were included only when differential expression from P7-Adult was significant (p < 0.05) by all three methods (DEseq2, EdgeR, and Bayseq)

Mentions: Inspection of expression levels by postnatal age at the single gene level revealed that their maturational trajectories from P7 to adulthood had different profiles. To capture the main patterns, expression trend analyses were carried out to identify and tally genes with four different profiles types: monotonically increasing or decreasing, static, and other (Fig. 4, Table 5). A profile was monotonically “increasing” if expression increased successively at each time point and the change between P7 and adult was statistically significant. Monotonically “decreasing” genes were defined in the same fashion, but with decreased expression at each time point. Genes with flat trajectories across all ages were defined as “static”, and those with other patterns of expression (e.g., increasing, then decreasing or decreasing, then increasing) were categorized as “other”. The total numbers of genes with monotonically increasing or decreasing profiles was comparable in A1 (15.3 %) and MG (20.4 %). Of these, nearly equal numbers of genes had increasing and decreasing trajectories in A1, whereas 85.2 % of genes in MG had decreasing trajectories. In comparison to the monotonically changing profile types, the numbers of genes with “static” or “other” profiles were much greater, and similar in both regions. As will be noted in Figs. 5, 6, 7 and 8, a frequently observed profile in the “other” category was characterized by upregulation between P7 and P14 or P14 and P21, followed by downregulation at a subsequent age. Finally, in the third data series (A1 / MG), the number of genes that were differentially expressed in both A1 and MG (i.e., common to both regions) was given for each profile type. These numbers were a variable fraction (between 15 % and 64 %) of the total numbers in either region, depending on the profile. A possible interpretation is that expression of genes with the same maturational trajectory in both regions may be governed by similar factors.Table 5


Transcriptional maturation of the mouse auditory forebrain.

Hackett TA, Guo Y, Clause A, Hackett NJ, Garbett K, Zhang P, Polley DB, Mirnics K - BMC Genomics (2015)

Gene expression profiles of the synaptic vesicle exocytosis gene ontology category. Gene expression profiles are plotted for a subset of genes from one gene ontology category, selected from the GSEA analysis in Table 7 (GO: 0016079, synaptic vesicle exocytosis). For each gene, mean normalized counts and % of maximum counts are plotted by postnatal age (P7, P14, P21, Adult) and brain region (A1, MG). Expression trajectory is indicated by arrows (up, down, none). Arrows were included only when differential expression from P7-Adult was significant (p < 0.05) by all three methods (DEseq2, EdgeR, and Bayseq)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4536593&req=5

Fig5: Gene expression profiles of the synaptic vesicle exocytosis gene ontology category. Gene expression profiles are plotted for a subset of genes from one gene ontology category, selected from the GSEA analysis in Table 7 (GO: 0016079, synaptic vesicle exocytosis). For each gene, mean normalized counts and % of maximum counts are plotted by postnatal age (P7, P14, P21, Adult) and brain region (A1, MG). Expression trajectory is indicated by arrows (up, down, none). Arrows were included only when differential expression from P7-Adult was significant (p < 0.05) by all three methods (DEseq2, EdgeR, and Bayseq)
Mentions: Inspection of expression levels by postnatal age at the single gene level revealed that their maturational trajectories from P7 to adulthood had different profiles. To capture the main patterns, expression trend analyses were carried out to identify and tally genes with four different profiles types: monotonically increasing or decreasing, static, and other (Fig. 4, Table 5). A profile was monotonically “increasing” if expression increased successively at each time point and the change between P7 and adult was statistically significant. Monotonically “decreasing” genes were defined in the same fashion, but with decreased expression at each time point. Genes with flat trajectories across all ages were defined as “static”, and those with other patterns of expression (e.g., increasing, then decreasing or decreasing, then increasing) were categorized as “other”. The total numbers of genes with monotonically increasing or decreasing profiles was comparable in A1 (15.3 %) and MG (20.4 %). Of these, nearly equal numbers of genes had increasing and decreasing trajectories in A1, whereas 85.2 % of genes in MG had decreasing trajectories. In comparison to the monotonically changing profile types, the numbers of genes with “static” or “other” profiles were much greater, and similar in both regions. As will be noted in Figs. 5, 6, 7 and 8, a frequently observed profile in the “other” category was characterized by upregulation between P7 and P14 or P14 and P21, followed by downregulation at a subsequent age. Finally, in the third data series (A1 / MG), the number of genes that were differentially expressed in both A1 and MG (i.e., common to both regions) was given for each profile type. These numbers were a variable fraction (between 15 % and 64 %) of the total numbers in either region, depending on the profile. A possible interpretation is that expression of genes with the same maturational trajectory in both regions may be governed by similar factors.Table 5

Bottom Line: Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age.Maturational changes are evident at the global through single gene levels.The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.

View Article: PubMed Central - PubMed

Affiliation: Department of Hearing and Speech Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA. troy.a.hackett@vanderbilt.edu.

ABSTRACT

Background: The maturation of the brain involves the coordinated expression of thousands of genes, proteins and regulatory elements over time. In sensory pathways, gene expression profiles are modified by age and sensory experience in a manner that differs between brain regions and cell types. In the auditory system of altricial animals, neuronal activity increases markedly after the opening of the ear canals, initiating events that culminate in the maturation of auditory circuitry in the brain. This window provides a unique opportunity to study how gene expression patterns are modified by the onset of sensory experience through maturity. As a tool for capturing these features, next-generation sequencing of total RNA (RNAseq) has tremendous utility, because the entire transcriptome can be screened to index expression of any gene. To date, whole transcriptome profiles have not been generated for any central auditory structure in any species at any age. In the present study, RNAseq was used to profile two regions of the mouse auditory forebrain (A1, primary auditory cortex; MG, medial geniculate) at key stages of postnatal development (P7, P14, P21, adult) before and after the onset of hearing (~P12). Hierarchical clustering, differential expression, and functional geneset enrichment analyses (GSEA) were used to profile the expression patterns of all genes. Selected genesets related to neurotransmission, developmental plasticity, critical periods and brain structure were highlighted. An accessible repository of the entire dataset was also constructed that permits extraction and screening of all data from the global through single-gene levels. To our knowledge, this is the first whole transcriptome sequencing study of the forebrain of any mammalian sensory system. Although the data are most relevant for the auditory system, they are generally applicable to forebrain structures in the visual and somatosensory systems, as well.

Results: The main findings were: (1) Global gene expression patterns were tightly clustered by postnatal age and brain region; (2) comparing A1 and MG, the total numbers of differentially expressed genes were comparable from P7 to P21, then dropped to nearly half by adulthood; (3) comparing successive age groups, the greatest numbers of differentially expressed genes were found between P7 and P14 in both regions, followed by a steady decline in numbers with age; (4) maturational trajectories in expression levels varied at the single gene level (increasing, decreasing, static, other); (5) between regions, the profiles of single genes were often asymmetric; (6) GSEA revealed that genesets related to neural activity and plasticity were typically upregulated from P7 to adult, while those related to structure tended to be downregulated; (7) GSEA and pathways analysis of selected functional networks were not predictive of expression patterns in the auditory forebrain for all genes, reflecting regional specificity at the single gene level.

Conclusions: Gene expression in the auditory forebrain during postnatal development is in constant flux and becomes increasingly stable with age. Maturational changes are evident at the global through single gene levels. Transcriptome profiles in A1 and MG are distinct at all ages, and differ from other brain regions. The database generated by this study provides a rich foundation for the identification of novel developmental biomarkers, functional gene pathways, and targeted studies of postnatal maturation in the auditory forebrain.

No MeSH data available.


Related in: MedlinePlus