"Meiosis arrester" C-natriuretic peptide directly stimulates oocyte mtDNA accumulation and is implicated in aging-associated oocyte mtDNA loss.

C-natriuretic peptide (CNP) is the central regulator of oocyte meiosis progression, thus coordinating synchronization of oocyte nuclear-cytoplasmic maturation. However, whether CNP can independently regulate cytoplasmic maturation has been long overlooked. Mitochondrial DNA (mtDNA) accumulation is the hallmark event of cytoplasmic maturation, but the mechanism underlying oocyte mtDNA replication remains largely elusive. Herein, we report that CNP can directly stimulate oocyte mtDNA replication at GV stage, and deficiency of follicular CNP may contribute largely to lower mtDNA copy number in in vitro matured oocytes. The mechanistic study showed that cAMP-PKA-CREB1 signaling cascade underlies the regulatory role of CNP in stimulating mtDNA replication and upregulating related genes. Of interest, we also report that CNP-NPR2 signaling is inhibited in aging follicles, and this inhibition is implicated in lower mtDNA copy number in oocytes from aging females. Together, our study provides the first direct functional link between follicular CNP and oocyte mtDNA replication, and identifies its involvement in aging-associated mtDNA loss in oocytes. These findings, not only update the current knowledge of the functions of CNP in coordinating oocyte maturation but also present a promising strategy for improving in vitro fertilization outcomes of aging females.

The SIK1/CRTC2/CREB1 and TWIST1/PI3K/Akt/GSK3ß signaling pathways mediated by microRNA-25-3p are altered in the schizophrenic rat brain.

Schizophrenia is a group of severe mental disorders. MiR-25-3p was shown to be involved in various neuropsychiatric diseases and can regulate SIK1 and TWIST1. The CRTC2/CREB1 and PI3K/Akt/GSK3ß signaling pathways are downstream pathways of SIK1 and TWIST1, respectively. This study investigated whether miR-25-3p-mediated SIK1/CRTC2/CREB1 and TWIST1/PI3K/Akt/GSK3ß signaling pathways are present in an animal model relevant to schizophrenia. A schizophrenic rat model was established by using sub-chronic MK-801 administration. An RNA-seq test was performed to examine the differentially expressed genes (DEGs) in the rat prefrontal cortex (PFC). The mRNA levels of miR-25-3p, SIK1, and TWIST in the PFC and caudate putamen (CPu) were assessed by qRT-PCR. Phosphorylation of the SIK1/CRTC2/CREB1 and TWIST1/PI3K/Akt/GSK3ß pathways in the two brain regions was examined by Western blots. The RNA-seq data revealed down-regulated miR-25-3p expression and up-regulated SIK1 and TWIST1 mRNA expression induced by MK-801. Additionally, SIK1 and TWIST1 were shown to be possible downstream responders of miR-25-3p in previous studies. qRT-PCR confirmed the changes of miR-25-3p, SIK1, and TWIST1 induced by MK-801 in both brain regions, which, however, was reversed by risperidone. Furthermore, the phosphorylation of the SIK1/CRTC2/CREB1 pathway was repressed by MK-801, whereas the phosphorylation of the TWIST1/PI3K/Akt/GSK3ß pathway was increased by MK-801 in either of the two brain regions. Moreover, the altered phosphorylation of these two signaling pathways induced by MK-801 can be restored by risperidone. In conclusion, this study suggests that altered SIK1/CRTC2/CREB1 and TWIST1/PI3K/Akt/GSK3ß signaling pathways mediated by miR-25-3p is very likely to be associated with schizophrenia, revealing potential targets for the treatment and clinical diagnosis of schizophrenia.

sAPPß and sAPPα increase structural complexity and E/I input ratio in primary hippocampal neurons and alter Ca2+ homeostasis and CREB1-signaling.

One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid ß (Aß). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aß production and soluble APPß (sAPPß) levels. Aß is known to impair synaptic function; however, much less is known about the physiological functions of sAPPß. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPß exist. The intracellular pathways of sAPPß are largely unknown. Since sAPPß is generated alongside Aß by ß-secretase (BACE1) cleavage, we tested the hypothesis that sAPPß effects differ from sAPPα effects as a neurotrophic factor. We therefore performed a head-to-head comparison of both mammalian recombinant peptides in developing primary hippocampal neurons (PHN). We found that sAPPα significantly increases axon length (p = 0.0002) and that both sAPPα and sAPPß increase neurite number (p < 0.0001) of PHN at 7 days in culture (DIV7) but not at DIV4. Moreover, both sAPPα- and sAPPß-treated neurons showed a higher neuritic complexity in Sholl analysis. The number of glutamatergic synapses (p < 0.0001), as well as layer thickness of postsynaptic densities (PSDs), were significantly increased, and GABAergic synapses decreased upon sAPP overexpression in PHN. Furthermore, we showed that sAPPα enhances ERK and CREB1 phosphorylation upon glutamate stimulation at DIV7, but not DIV4 or DIV14. These neurotrophic effects are further associated with increased glutamate sensitivity and CREB1-signaling. Finally, we found that sAPPα levels are significantly reduced in brain homogenates of AD patients compared to control subjects. Taken together, our data indicate critical stage-dependent roles of sAPPs in the developing glutamatergic system in vitro, which might help to understand deleterious consequences of altered APP shedding in AD patients, beyond Aß pathophysiology.