Rpph1 Upregulates CDC42 Expression and Promotes Hippocampal Neuron Dendritic Spine Formation by Competing with miR-330-5p

Abstract

Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disease. Recent studies employing microRNA-seq and genome-wide sequencing have identified some non-coding RNAs that are influentially involved in AD pathogenesis. Non-coding RNAs can compete with other endogenous RNAs by microRNA response elements (MREs) and manipulate biological processes, such as tumorigenesis. However, only a few non-coding RNAs have been reported in the pathogenesis of AD. In this study, we constructed the first competing endogenous RNA (ceRNA) network leveraging whole transcriptome sequencing and a previously studied microRNA-seq of APPswe/PS1ΔE9 transgenic mice. The underlying mechanisms for the involvement of ceRNA in AD were validated using the Dual Luciferase Reporter Assay, detection of transcription levels by quantitative RT-PCR and translation levels by Western blotting, and morphological examination in primary cultured neurons. In the ceRNA network, four lncRNAs (C030034L19Rik, Rpph1, A830012C17Rik, and Gm15477) and five miRNAs (miR-182-5p, miR-330-5p, miR-326-3p, miR-132-3p, and miR-484) are enriched in nine pathways and an AD-related gene pool. Among them, Ribonuclease P RNA component H1 (Rpph1) is upregulated in the cortex of APPswe/PS1ΔE9 mice compared to wild type controls. Rpph1 binds to miR326-3p/miR-330-5p and causes the release of their downstream target Cdc42, which leads to CDC42 upregulation. This effect was disrupted upon mutation of the MRE on Rpph1. Moreover, overexpression of Rpph1 increased dendritic spine density in primary cultured hippocampal pyramidal neurons, whereas knocking down of Rpph1 had the reverse effect. In conclusion, Rpph1 modulates CDC42 expression level in a ceRNA-dependent manner, which may represent a compensatory mechanism in the early stage of the AD pathogenesis.

Knockdown of Foxg1 in supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse cochlea

“…To activate the Cre enzyme, postnatal day (P)1 or P3 mice were injected with tamoxifen (Sigma) intraperitoneally (I.P.) (1.5 mg/25 g body weight for Sox2-CreER mice, 3.5 mg/25 g body weight for Lgr5-CreER mice, and 2 mg/25 g body weight for Sox9-CreER mice, which were all consistent with previous reports [4,73,74]). For each experiment, the control mice were also injected with the same amount of tamoxifen.…”

“…The Foxg1-floxp mice were a gift from Prof. Chunjie Zhao from Southeast University [24]. Sox9-IRES-CreER mice were a gift from Prof. Fengchao Wang from the National Institute of Biological Sciences (NIBS), Beijing [73]. We performed all animal procedures according to protocols that were approved by the Animal Care and Use Committee of Southeast University and that were consistent with the National Institute of Health's Guide for the Care and Use of Laboratory Animals.…”

MicroRNA profiles of MS gray matter lesions identify modulators of the synaptic protein synaptotagmin‐7

“…Interestingly, the occurrence in neurons has been described for the miRNAs miR-330 (14) and miR574 (49) and some miRNAs of the let-7 family (58,60,74,94,101).…”

Inhibition of breast cancer cell proliferation and tumorigenesis by long non-coding RNA RPPH1 down-regulation of miR-122 expression

“…RPPH1 is a well-known RNA subunit of RNase P, which is responsible for tRNA maturation in all three domains of life [ 17 ]. A previous study demonstrated that one of our tested ceRNA pathways, RPPH1 /miR-330-5p/CDC42, may be involved in the compensatory behaviour of brain neurons to combat synaptic loss during AD pathogenesis [ 18 ]. However, the downstream pathway in breast cancer is currently not known.…”