Transcriptomic Analysis of the Aged Nulliparous Mouse Ovary Suggests a Stress State That Promotes Pro-Inflammatory Lipid Signaling and Epithelial Cell Enrichment.

Ovarian cancer (OC) incidence and mortality peaks at post-menopause while OC risk is either reduced by parity or increased by nulliparity during fertile life. The long-term effect of nulliparity on ovarian gene expression is largely unknown. In this study, we describe a bioinformatic/data-mining analysis of 112 coding genes upregulated in the aged nulliparous (NP) mouse ovary compared to the aged multiparous one as reference. Canonical gene ontology and pathway analyses indicated a pro-oxidant, xenobiotic-like state accompanied by increased metabolism of inflammatory lipid mediators. Up-regulation of typical epithelial cell markers in the aged NP ovary was consistent with synchronized overexpression of Cldn3, Ezr, Krt7, Krt8 and Krt18 during the pre-neoplastic phase of mOSE cell cultures in a former transcriptome study. In addition, 61/112 genes were upregulated in knockout mice for Fshr and for three other tumor suppressor genes (Pten, Cdh1 and Smad3) known to regulate follicular homeostasis in the mammalian ovary. We conclude that the aged NP ovary displays a multifaceted stress state resulting from oxidative imbalance and pro-inflammatory lipid signaling. The enriched epithelial cell content might be linked to follicle depletion and is consistent with abundant clefts and cysts observed in aged human and mouse ovaries. It also suggests a mesenchymal-to-epithelial transition in the mOSE of the aged NP ovary. Our analysis suggests that in the long term, nulliparity worsens a variety of deleterious effects of aging and senescence thereby increasing susceptibility to cancer initiation in the ovary.

Analysis of the early response to spinal cord injury identified a key role for mTORC1 signaling in the activation of neural stem progenitor cells.

Xenopus laevis are able to regenerate the spinal cord during larvae stages through the activation of neural stem progenitor cells (NSPCs). Here we use high-resolution expression profiling to characterize the early transcriptome changes induced after spinal cord injury, aiming to identify the signals that trigger NSPC proliferation. The analysis delineates a pathway that starts with a rapid and transitory activation of immediate early genes, followed by migration processes and immune response genes, the pervasive increase of NSPC-specific ribosome biogenesis factors, and genes involved in stem cell proliferation. Western blot and immunofluorescence analysis showed that mTORC1 is rapidly and transiently activated after SCI, and its pharmacological inhibition impairs spinal cord regeneration and proliferation of NSPC through the downregulation of genes involved in the G1/S transition of cell cycle, with a strong effect on PCNA. We propose that the mTOR signaling pathway is a key player in the activation of NPSCs during the early steps of spinal cord regeneration.