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Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders.

Ander BP, Barger N, Stamova B, Sharp FR, Schumann CM - Mol Autism (2015)

Bottom Line: We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, MIND Institute, University of California at Davis Medical Center, 2805 50th Street, Sacramento, CA 95817 USA.

ABSTRACT

Background: Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Abnormalities in individual regulatory small non-coding RNA (sncRNA), including microRNA (miRNA), could have profound effects upon multiple functional pathways. We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).

Methods: We measured sncRNA expression levels in 34 samples of postmortem brain from STS and PAC to find differentially expressed sncRNA in ASD compared with control cases. For differentially expressed miRNA, we further analyzed their predicted mRNA targets and carried out functional over-representation analysis of KEGG pathways to examine their functional significance and to compare our findings to reported alterations in ASD gene expression.

Results: Two mature miRNAs (miR-4753-5p and miR-1) were differentially expressed in ASD relative to control in STS and four (miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297) in PAC. In both regions, miRNA were functionally related to various nervous system, cell cycle, and canonical signaling pathways, including PI3K-Akt signaling, previously implicated in ASD. Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.

Conclusions: Alterations in sncRNA may underlie dysregulation of molecular pathways implicated in autism. sncRNA transcriptional abnormalities in ASD were apparent in STS and in PAC, a brain region not directly associated with core behavioral impairments. Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

No MeSH data available.


Related in: MedlinePlus

Sampling of brain regions. Schematic of the human brain indicating regions of the superior temporal gyrus sampled—superior temporal sulcus (STS - orange) and primary auditory cortex (PAC - teal). A section from the caudal portion of the temporal lobe was utilized for each case (the approximate position is noted by the dashed lines). In the same coronal section, tissue blocks for the PAC (dark teal) were sampled from Heschl’s gyrus (light teal) and blocks for the STS (dark orange) were sampled from the upper wall of the STS (light orange)
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Fig1: Sampling of brain regions. Schematic of the human brain indicating regions of the superior temporal gyrus sampled—superior temporal sulcus (STS - orange) and primary auditory cortex (PAC - teal). A section from the caudal portion of the temporal lobe was utilized for each case (the approximate position is noted by the dashed lines). In the same coronal section, tissue blocks for the PAC (dark teal) were sampled from Heschl’s gyrus (light teal) and blocks for the STS (dark orange) were sampled from the upper wall of the STS (light orange)

Mentions: This study was exempt from human subjects review by the Internal Review Board at the UC Davis School of Medicine. Donor brain tissue was obtained from the Autism Tissue Program collection previously housed at the Harvard Brain Tissue Resource Center (http://www.mcleanhospital.org/research-programs/harvard-brain-tissue-resource-center). Postmortem Confirmation of Consent was provided by next-of-kin and held along with identifiable personal health information by the Autism Tissue Program. A total of 36 samples were obtained from ten ASD and eight control subjects. Individual and summarized subject demographics are presented in Table 1. One STS and one PAC sample were taken from the same frozen coronal brain section of each donor brain. The primary auditory cortex (PAC) sample included the primary sensory areas of Brodmann’s areas 41 and 42 and was taken from the crown of Heschl’s gyrus (Fig. 1), where it is reliably found as indicated by functional and cytoarchitectonic maps [24]. Samples from the superior temporal sulcus (STS) included the polymodal association cortex of Brodmann’s area 22 and were taken from the upper wall of the superior temporal sulcus immediately opposite Heschl’s gyrus [25, 26] (Fig. 1).Table 1


Atypical miRNA expression in temporal cortex associated with dysregulation of immune, cell cycle, and other pathways in autism spectrum disorders.

Ander BP, Barger N, Stamova B, Sharp FR, Schumann CM - Mol Autism (2015)

Sampling of brain regions. Schematic of the human brain indicating regions of the superior temporal gyrus sampled—superior temporal sulcus (STS - orange) and primary auditory cortex (PAC - teal). A section from the caudal portion of the temporal lobe was utilized for each case (the approximate position is noted by the dashed lines). In the same coronal section, tissue blocks for the PAC (dark teal) were sampled from Heschl’s gyrus (light teal) and blocks for the STS (dark orange) were sampled from the upper wall of the STS (light orange)
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4491207&req=5

Fig1: Sampling of brain regions. Schematic of the human brain indicating regions of the superior temporal gyrus sampled—superior temporal sulcus (STS - orange) and primary auditory cortex (PAC - teal). A section from the caudal portion of the temporal lobe was utilized for each case (the approximate position is noted by the dashed lines). In the same coronal section, tissue blocks for the PAC (dark teal) were sampled from Heschl’s gyrus (light teal) and blocks for the STS (dark orange) were sampled from the upper wall of the STS (light orange)
Mentions: This study was exempt from human subjects review by the Internal Review Board at the UC Davis School of Medicine. Donor brain tissue was obtained from the Autism Tissue Program collection previously housed at the Harvard Brain Tissue Resource Center (http://www.mcleanhospital.org/research-programs/harvard-brain-tissue-resource-center). Postmortem Confirmation of Consent was provided by next-of-kin and held along with identifiable personal health information by the Autism Tissue Program. A total of 36 samples were obtained from ten ASD and eight control subjects. Individual and summarized subject demographics are presented in Table 1. One STS and one PAC sample were taken from the same frozen coronal brain section of each donor brain. The primary auditory cortex (PAC) sample included the primary sensory areas of Brodmann’s areas 41 and 42 and was taken from the crown of Heschl’s gyrus (Fig. 1), where it is reliably found as indicated by functional and cytoarchitectonic maps [24]. Samples from the superior temporal sulcus (STS) included the polymodal association cortex of Brodmann’s area 22 and were taken from the upper wall of the superior temporal sulcus immediately opposite Heschl’s gyrus [25, 26] (Fig. 1).Table 1

Bottom Line: We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, MIND Institute, University of California at Davis Medical Center, 2805 50th Street, Sacramento, CA 95817 USA.

ABSTRACT

Background: Autism spectrum disorders (ASDs) likely involve dysregulation of multiple genes related to brain function and development. Abnormalities in individual regulatory small non-coding RNA (sncRNA), including microRNA (miRNA), could have profound effects upon multiple functional pathways. We assessed whether a brain region associated with core social impairments in ASD, the superior temporal sulcus (STS), would evidence greater transcriptional dysregulation of sncRNA than adjacent, yet functionally distinct, primary auditory cortex (PAC).

Methods: We measured sncRNA expression levels in 34 samples of postmortem brain from STS and PAC to find differentially expressed sncRNA in ASD compared with control cases. For differentially expressed miRNA, we further analyzed their predicted mRNA targets and carried out functional over-representation analysis of KEGG pathways to examine their functional significance and to compare our findings to reported alterations in ASD gene expression.

Results: Two mature miRNAs (miR-4753-5p and miR-1) were differentially expressed in ASD relative to control in STS and four (miR-664-3p, miR-4709-3p, miR-4742-3p, and miR-297) in PAC. In both regions, miRNA were functionally related to various nervous system, cell cycle, and canonical signaling pathways, including PI3K-Akt signaling, previously implicated in ASD. Immune pathways were only disrupted in STS. snoRNA and pre-miRNA were also differentially expressed in ASD brain.

Conclusions: Alterations in sncRNA may underlie dysregulation of molecular pathways implicated in autism. sncRNA transcriptional abnormalities in ASD were apparent in STS and in PAC, a brain region not directly associated with core behavioral impairments. Disruption of miRNA in immune pathways, frequently implicated in ASD, was unique to STS.

No MeSH data available.


Related in: MedlinePlus