Hippocampal Subregions Express Distinct Dendritic Transcriptomes that Reveal Differences in Mitochondrial Function in CA2

Farris, Shannon; Ward, James M.; Carstens, Kelly E.; Samadi, Mahsa; Wang, Yu; Dudek, Serena M.

doi:10.1016/j.celrep.2019.08.093

Cited by 78 publications

(101 citation statements)

References 104 publications

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“…Mouse RNA-sequencing and human microarray data RNA-Seq data were obtained from previously published work [66,67] (Gene Expression Omnibus Super-Series GSE116343). Briefly, laser capture microdissected samples (n = 3 per region) targeting the cell body region of CA1, CA2, CA3, and dentate gyrus were obtained and sequenced using an Illumina NextSeq 500 instrument, acquiring 100 bp paired-ends reads to a depth of 50 million reads per sample ( + /-10 mil).…”

Section: Single-molecule Fluorescent In Situ Hybridization and Image mentioning

confidence: 99%

“…Briefly, laser capture microdissected samples (n = 3 per region) targeting the cell body region of CA1, CA2, CA3, and dentate gyrus were obtained and sequenced using an Illumina NextSeq 500 instrument, acquiring 100 bp paired-ends reads to a depth of 50 million reads per sample ( + /-10 mil). Raw reads were pseudoaligned to GENCODE (vM12) gene models and the mm10 mouse genome and quantitated per gene using Salmon (v0.9.1, indexed with kmer size 31) [66][67][68]. The ratio of MR:GR was calculated from the normalized counts for each sample and averaged for each hippocampal subregion.…”

Section: Single-molecule Fluorescent In Situ Hybridization and Image mentioning

confidence: 99%

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Novel role for mineralocorticoid receptors in control of a neuronal phenotype

et al. 2019

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Mineralocorticoid receptors (MRs) in the brain play a role in learning and memory, neuronal differentiation, and regulation of the stress response. Within the hippocampus, the highest expression of MRs is in area CA2. CA2 pyramidal neurons have a distinct molecular makeup resulting in a plasticity-resistant phenotype, distinguishing them from neurons in CA1 and CA3. Thus, we asked whether MRs regulate CA2 neuron properties and CA2-related behaviors. Using three conditional knockout methods at different stages of development, we found a striking decrease in multiple molecular markers for CA2, an effect mimicked by chronic antagonism of MRs. Furthermore, embryonic deletion of MRs disrupted afferent inputs to CA2 and enabled synaptic potentiation of the normally LTP-resistant synaptic currents in CA2. We also found that CA2-targeted MR knockout was sufficient to disrupt social behavior and alter behavioral responses to novelty. Altogether, these results demonstrate an unappreciated role for MRs in controlling CA2 pyramidal cell identity and in facilitating CA2-dependent behaviors.

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Section: Single-molecule Fluorescent In Situ Hybridization and Image mentioning

confidence: 99%

Section: Single-molecule Fluorescent In Situ Hybridization and Image mentioning

confidence: 99%

Novel role for mineralocorticoid receptors in control of a neuronal phenotype

et al. 2019

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“…Thus, distinct molecular pathways might convey the generation of neurons in these two structures. Moreover, several studies have shown that there is subregion specific transcriptional differences along the longitudinal axis [5,6,36]. Importantly, most of these studies exploit RNA sequencing approaches to investigate protein expression.…”

Section: Discussionmentioning

confidence: 99%

Physical Activity Dynamically Regulates the Hippocampal Proteome along the Dorso-Ventral Axis

Frey¹,

Schieweck²,

Forné³

et al. 2020

IJMS

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The hippocampus is central for higher cognition and emotions. In patients suffering from neuropsychiatric or neurodegenerative diseases, hippocampal signaling is altered causing cognitive defects. Thus, therapeutic approaches aim at improving cognition by targeting the hippocampus. Enhanced physical activity (EPA) improves cognition in rodents and humans. A systematic screen, however, for expression changes in the hippocampus along the dorso-ventral axis is missing, which is a prerequisite for understanding molecular mechanisms. Here, we exploited label free mass spectrometry to detect proteomic changes in the hippocampus of male mice upon voluntary wheel running. To identify regional differences, we examined dorsal and ventral CA1, CA3 and dentate gyrus hippocampal subregions. We found metabolic enzymes and actin binding proteins, such as RhoA, being upregulated in the hippocampus upon EPA suggesting a coordination between metabolism and cytoskeleton remodeling; two pathways essential for synaptic plasticity. Strikingly, dorsal and ventral hippocampal subregions respond differentially to EPA. Together, our results provide new insight into proteomic adaptations driven by physical activity in mice. In addition, our results suggest that dorsal and ventral hippocampus, as well as hippocampal subregions themselves, contribute differently to this process. Our study therefore provides an important resource for studying hippocampal subregion diversity in response to EPA.

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“…However, it has been unclear how widespread this effect is and whether it was driven primarily by tandem UTRs or ALEs. To address this, we used LABRAT to analyze the relative APA status of 26 paired transcriptomic datasets from cell body and projection samples from neuronal cells, NIH 3T3 cells, and MDA-MB231 cells (Farris et al, 2019;Goering et al, 2019;Hudish et al, 2020;Mardakheh et al, 2015;Minis et al, 2013;Taliaferro et al, 2016;Tushev et al, 2018;Wang et al, 2017;Zappulo et al, 2017).…”

Section: Alternative Polyadenylation Isoforms Are Differentially Locamentioning

confidence: 99%

LABRAT reveals association of alternative polyadenylation with transcript localization, RNA binding protein expression, transcription speed, and cancer survival

Goering

Engel

Gillen

et al. 2020

Preprint

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The sequence content of the 3′ UTRs of many mRNA transcripts is regulated through alternative polyadenylation (APA). The study of this process using RNAseq data, though, has been historically challenging. To combat this problem, we developed LABRAT, an APA quantification method. LABRAT takes advantage of newly developed transcriptome quantification techniques to accurately determine relative APA site usage and how it varies across conditions. Using LABRAT, we found consistent relationships between gene-distal APA and subcellular RNA localization in multiple cell types. We also observed connections between transcription speed and APA site choice as well as tumor-specific transcriptome-wide shifts in APA in hundreds of patient-derived tumor samples that were associated with patient prognosis. We investigated the effects of APA on transcript expression and found a weak overall relationship, although many individual genes showed strong correlations between APA and expression. We interrogated the roles of 191 RNA-binding proteins in the regulation of APA, finding that dozens promote broad, directional shifts in relative APA isoform abundance both in vitro and in patient-derived samples. Finally, we find that APA site shifts in the two classes of APA, tandem UTRs and alternative last exons, are strongly correlated across many contexts, suggesting that they are coregulated.

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Hippocampal Subregions Express Distinct Dendritic Transcriptomes that Reveal Differences in Mitochondrial Function in CA2

Cited by 78 publications

References 104 publications

Novel role for mineralocorticoid receptors in control of a neuronal phenotype

Novel role for mineralocorticoid receptors in control of a neuronal phenotype

Physical Activity Dynamically Regulates the Hippocampal Proteome along the Dorso-Ventral Axis

LABRAT reveals association of alternative polyadenylation with transcript localization, RNA binding protein expression, transcription speed, and cancer survival

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