miR-17-92 Cluster Regulates Adult Hippocampal Neurogenesis, Anxiety, and Depression

Jin, Junghee; Kim, Seung-Nam; Liu, Xuqing; Zhang, Haijun; Zhang, Chao; Seo, Ji-Seon; Kim, Yong; Sun, Tao

doi:10.1016/j.celrep.2016.06.101

Cited by 94 publications

(91 citation statements)

References 46 publications

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“…Depression resulting from miR-17∼92 knockout in adult NPCs 20 is a frequently occurring symptom in SZ patients 53 . Epilepsy, which often results in mis-localized adult-born neurons in the GCL, is a known risk factor for SZ 54-56 .…”

Section: Implications Of Mir-19 In Szmentioning

confidence: 99%

A role for miR-19 in the migration of adult-born neurons and schizophrenia

Han

Gage

2016

Neurogenesis

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The latest miRNA database (Release 21) annotated 2588 and 1915 miRNAs in the human and mouse genomes, respectively.1 However, the biological roles of miRNAs in vivo remain largely unknown. In particular, the physiological and pathological roles of individual microRNAs in the brain have not been investigated extensively although expression profiles of microRNAs have been reported in many given conditions. In a recent study,2 we identified miR-19, which is enriched in adult hippocampal neural progenitor cells (NPCs), as a key regulator for adult hippocampal neurogenesis. miR-19 is an intrinsic factor regulating the migration of newborn neurons by modulating expression level of RAPGEF2. After observing the abnormal expression patterns of miR-19 and RAPGEF2 in NPCs derived from induced pluripotent stem cells of schizophrenic patients, which display aberrant cell migration, we proposed miR-19 as a molecule associated with schizophrenia. The results illustrate that a single microRNA has the potential to impact the functions of the brain. Identifying miRNA-mediated posttranscriptional gene regulation in the brain will expand our understanding of brain development and functions and the etiologies of several brain disorders.

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Section: Implications Of Mir-19 In Szmentioning

confidence: 99%

A role for miR-19 in the migration of adult-born neurons and schizophrenia

Han

Gage

2016

Neurogenesis

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“…The primer used for mutagenesis was: miR-19a-mut, 5’–GCA GCC CTC TGT TAG TTT TGC ATA GTA GAG TAC AAG AAG AAT GTA GTT CTA CTA ATC TAT CAA AAC TGA TGG TGG CCT GC–3’. To generate miRNA expression constructs, miR-19a fragment was inserted into the pcDNA3.1 as described [18, 19]. Plasmids were quantified by Nanodrop 2000c Spec-trophotometer (Thermo Fisher Scientific, USA), and then transfected into 293T cells using Lipofectamine 3000 (Invitrogen, USA) according to the manufacturer’s protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Emerging evidence has shown that this cluster is essential for many developmental and pathogenic processes [15], such as type B lymphopoiesis [16], lung development [16], heart development [17], neurogenesis [18, 19] and tumorigenesis [20]. It is involved in the processes of cell proliferation, apoptosis, differentiation and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

Wang

Tian

et al. 2018

Cell Physiol Biochem

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Background/Aims: Oogenesis is a highly complex process that is intricately regulated by interactions of multiple genes and signaling molecules. However, the underlying molecular mechanisms are poorly understood. There is emerging evidence that microRNAs contribute to oogenesis. Here, we aimed to investigate the role of miR-17-92 cluster in regulating oogenesis. Methods: The miR-17-92 cluster was genetically ablated in germ cells of female mice by applying the Cre-loxp system for conditional gene knockout. Mating experiment, superovulation and histological analysis were used to assess the fertility of the model female mice. TUNEL assay was used to identify apoptotic cells in ovaries. The expression level of apoptosis- and follicular atresia- related genes was evaluated by qRT-PCR. Western blotting was performed to detect protein expression. Bioinformatics software and dual luciferase reporter assay were applied to predict and verify the target of miR-17-92 cluster. Results: Deletion of miR-17-92 cluster in germ cells of female mice caused increased oocyte degradation and follicular atresia, perturbed oogenesis, and ultimately led to subfertility. Genes involved in follicular atresia and the mitochondrial apoptotic pathway were obviously up-regulated. Furthermore, we verified that miR-19a regulated oogenesis at the post-transcriptional level by targeting Bmf in the ovaries of miR-17-92 cluster conditional knockout female mice. Conclusion: The miR-17-92 cluster is an important regulator of oogenesis. These findings will assist in better understanding the etiology of disorders in oogenesis and in developing new therapeutic targets for female infertility.

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“…Recent findings have demonstrated a causal role for specific miRNAs in mediating stress coping behavior. Mice with miR-17–92 knocked out display increased reactive coping on forced-swim and tail-suspension tests [46], while mice with miR-34 knocked out display resilience to chronic mild stress [47]. However, none of these genetic manipulations have yet to take into account region-specific miRNA expression.…”

Section: Introductionmentioning

confidence: 99%

Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats

Cohen

Ata

Jackson

et al. 2017

Behavioural Brain Research

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Chronic stress triggers a variety of physical and mental health problems, and how individuals cope with stress influences risk for emotional disorders. To investigate molecular mechanisms underlying distinct stress coping styles, we utilized rats that were selectively-bred for differences in emotionality and stress reactivity. We show that high novelty responding (HR) rats readily bury a shock probe in the defensive burying test, a measure of proactive stress coping behavior, while low novelty responding (LR) rats exhibit enhanced immobility, a measure of reactive coping. Shock exposure in the defensive burying test elicited greater activation of HR rats’ caudal dorsal raphe serotonergic cells compared to LRs, but lead to more pronounced activation throughout LRs’ amygdala (lateral, basolateral, central, and basomedial nuclei) compared to HRs. RNA-sequencing revealed 271 mRNA transcripts and 33 microRNA species that were differentially expressed in HR/LR raphe and amygdala. We mapped potential microRNA-mRNA networks by correlating and clustering mRNA and microRNA expression and identified networks that differed in either the HR/LR dorsal raphe or amygdala. A dorsal raphe network linked three microRNAs which were down-regulated in LRs (miR-206-3p, miR-3559-5p, and miR-378a-3p) to repression of genes related to microglia and immune response (Cd74, Cyth4, Nckap1l, and Rac2), the genes themselves were up-regulated in LR dorsal raphe. In the amygdala, another network linked miR-124-5p, miR-146a-5p, miR-3068-3p, miR-380-5p, miR-539-3p, and miR-7a-1-3p with repression of chromatin remodeling-related genes (Cenpk, Cenpq, Itgb3bp, and Mis18a). Overall this work highlights potential drivers of gene-networks and downstream molecular pathways within the raphe and amygdala that contribute to individual differences in stress coping styles and stress vulnerabilities.

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miR-17-92 Cluster Regulates Adult Hippocampal Neurogenesis, Anxiety, and Depression

Cited by 94 publications

References 46 publications

A role for miR-19 in the migration of adult-born neurons and schizophrenia

A role for miR-19 in the migration of adult-born neurons and schizophrenia

Ablation of the MiR-17-92 MicroRNA Cluster in Germ Cells Causes Subfertility in Female Mice

Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats

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