KRAS is required for placenta development

Besides its well-known roles in cancer, KRAS is important for embryogenesis, as its absence causes embryonic lethality. The precise mechanisms underlying the developmental functions of KRAS is still incompletely characterized. To address this issue, we analyzed Kras-/- mouse embryos. We observed that Kras-/- embryos show a lethality that starts around E13.5. Interestingly, a placental phenotype was observed in Kras-/- embryos. This phenotype was associated with a small placental size, and a marked decrease in glycogen trophoblast cells. It was related to the presence of hypoglycaemia and hypoxia in Kras-/- embryos. Thus, our study reveals hidden functions of KRAS4. Importantly, it identifies for the first time a role for KRAS in the differentiation process of a specific cell type and the biological defects caused by a loss of KRAS. Wild-type and Kras-/- mouse placenta were collected at e13.5. Cell nuclei were purified, RNA was extracted and submitted to snRNAseq.除了其在癌症中广为人知的功能外，KRAS（Kirsten大鼠肉瘤病毒癌基因同源物）在胚胎发生过程中同样发挥关键作用，其缺失会导致胚胎致死。目前，KRAS在胚胎发育过程中发挥功能的精确分子机制仍未被完全阐明。为解决这一科学问题，本研究对Kras基因纯合敲除（Kras-/-）小鼠胚胎进行了分析。我们观察到，Kras-/-小鼠胚胎的致死现象大约始于胚胎发育第13.5天（E13.5）。值得注意的是，我们在Kras-/-小鼠胚胎中发现了胎盘表型异常：该表型伴随胎盘体积偏小，糖原滋养层细胞数量显著减少，且与Kras-/-小鼠胚胎存在低血糖及缺氧状态密切相关。综上，本研究揭示了KRAS4此前未被报道的隐匿性功能。尤为重要的是，本研究首次证实了KRAS在特定细胞类型分化过程中的作用，以及KRAS缺失所引发的生物学缺陷。本研究于胚胎发育第13.5天（E13.5）收集了野生型及Kras-/-小鼠的胎盘组织，随后纯化细胞核、提取RNA并开展单细胞核RNA测序（single-nucleus RNA sequencing, snRNAseq）。