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The transcription coactivator YAP1 mediates the major effects of the Hippo signaling pathway. The CCN family is a small group of glycoproteins known to be downstream effectors of YAP1 in diverse tissues. However, whether CCN family members mediate the effects of YAP1 in human trophoblasts is unknown. In this study, placental expression of both YAP1and CCN1was found to be impaired in pregnancies complicated by early-onset severe preeclampsia. CCN1 was expressed not only in cytotrophoblasts, trophoblast columns, and mesenchymal cells, similar to active YAP1, but also in syncytiotrophoblasts of normal first-trimester placental villi; moreover, decidual staining of active YAP1 and CCN1 was found in both interstitial and endovascular extravillous trophoblasts. In cultured immortalized human trophoblastic HTR-8/SVneo cells, knockdown of YAP1decreased CCN1mRNA and protein expression and led to impaired cell invasion and migration. Also, CCN1knockdown negatively affected HTR-8/SVneo cell invasion and migration but not viability. YAP1knockdown was further found to impair HTR-8/SVneo cell viability via G0/G1 cell cycle arrest and apoptosis, while CCN1knockdown had minimal effect on cell cycle arrest and no effect on apoptosis. Accordingly, treatment with recombinant CCN1 partially reversed the YAP1knockdown-induced impairment in trophoblast invasion and migration but not in viability. Thus, CCN1 mediates the effects of YAP1 on human trophoblast invasion and migration but not apoptosis, and decreased placental expression of YAP1and CCN1in pregnancies complicated by early-onset severe preeclampsia might contribute to the pathogenesis of this disease.CCN1 mediates the effects of YAP1 on human trophoblast invasion and migration but not on apoptosis. Decreased placental YAP1and CCN1expression in early-onset severe preeclampsia might contribute to the pathogenesis of this disease.Graphical AbstractDecreased placental YAP1 and CCN1 expression might contribute to the pathogenesis of early-onset sPE. Abnormally reduced expression of YAP1 in first-trimester placentas results in correspondingly decreased expression of CCN1 via transcriptional regulation by TEAD transcription factors; attenuated autocrine/paracrine effects of CCN1 on EVT invasion and migration might contribute to incomplete remodelling of uterine spiral arteries, which ultimately leads to early-onset sPE. CT, cytotrophoblast; ST, syncytiotrophoblast; TC, trophoblast column; EVT, extravillous trophoblast; iEVT, interstitial EVT; eEVT, endovascular EVT. This graphical abstract was generated using Illustrator CS6 (Adobe Systems) with some graphics from ScienceSlides 2016 (VisiScience, Chapel Hill, NC, USA).

Heat stress induces testicular oxidative stress, impairs spermatogenesis, and increases the risk of male infertility. Recent studies have highlighted the antioxidative properties of the Sestrins family in reducing cellular oxidative damage. However, the role of Sestrins (Sestrin1, 2, and 3) in the testicular response to heat stress remains unclear. Here, we found that Sestrin2 and 3 were highly expressed in the testis relative to Sestrin1. Then, the Sestrin2−/−and Sestrin3−/−mice were generated by CRISPR/Cas9 to investigate the role of them on spermatogenesis after heat stress. Our data showed that Sestrin2−/−and Sestrin3−/−mice testes exhibited more severe damage manifested by exacerbated loss of germ cells and higher levels of oxidative stress as compared to wild-type counterparts after heat stress. Notably, Sestrin2−/−and Sestrin3−/−mice underwent a remarkable increase in heat-induced spermatocyte apoptosis than that of controls. Furthermore, the transcriptome landscape of spermatocytes and chromosome spreading showed that loss of Sestrin2and Sestrin3exacerbated meiotic failure by compromising DNA double-strand breaks repair after heat stress. Taken together, our work demonstrated a critical protective function of Sestrin2 and Sestrin3 in mitigating the impairments of spermatogenesis against heat stress.Summary SentenceSestrin2 and Sestrin3 play an important role in safeguarding spermatogenesis against heat-induced meiotic defects, highlighting their importance in preserving male fertility after heat stress.Graphical Abstract