@article{4133cc88e1804f90bec3efa28aebba36,
title = "Cell-Cycle-Dependent ERK Signaling Dynamics Direct Fate Specification in the Mammalian Preimplantation Embryo",
abstract = "Despite the noisy nature of single cells, multicellular organisms robustly generate different cell types from one zygote. This process involves dynamic cross regulation between signaling and gene expression that is difficult to capture with fixed-cell approaches. To study signaling dynamics and fate specification during preimplantation development, we generated a transgenic mouse expressing the ERK kinase translocation reporter and measured ERK activity in single cells of live embryos. Our results show primarily active ERK in both the inner cell mass and trophectoderm cells due to fibroblast growth factor (FGF) signaling. Strikingly, a subset of mitotic events results in a short pulse of ERK inactivity in both daughter cells that correlates with elevated endpoint NANOG levels. Moreover, endogenous tagging of Nanog in embryonic stem cells reveals that ERK inhibition promotes enhanced stabilization of NANOG protein after mitosis. Our data show that cell cycle, signaling, and differentiation are coordinated during preimplantation development.",
keywords = "ERK, NANOG, blastocyst, cell cycle, embryonic stem cells, preimplantation development, signaling dynamics",
author = "Pokrass, {Michael J.} and Ryan, {Kathleen A.} and Tianchi Xin and Brittany Pielstick and Winston Timp and Valentina Greco and Sergi Regot",
note = "Funding Information: We thank all members of the Regot lab for helpful discussions and technical advice. We thank the Holland and Nathans lab for technical expertise and training in the handling of mice and collection of mouse embryos and the Hadjantonakis lab for training in the manipulation and culture of mouse blastocysts. We thank the Transgenic Animal Core Facility at JHSOM for performing pronuclear injection of mouse embryos and the Integrated Physiology Core at JHSOM for training and assistance in the culture of primary mouse enteroids. We acknowledge our funding sources: NIH T32 pre-doctoral training grants to M.P. and B.P., NSF Graduate Research Fellowships to M.P. ( DGE-1746891 ). An NSF CAREER award ( MCB-1844994 ), NIGMS R35 ( 1R35GM133499 ), American Cancer Society Research Scholar Grant ( 133537-RSG-19-005-01-CCG ), and Jerome L. Greene Foundation Discovery Award to S.R. Funding Information: We thank all members of the Regot lab for helpful discussions and technical advice. We thank the Holland and Nathans lab for technical expertise and training in the handling of mice and collection of mouse embryos and the Hadjantonakis lab for training in the manipulation and culture of mouse blastocysts. We thank the Transgenic Animal Core Facility at JHSOM for performing pronuclear injection of mouse embryos and the Integrated Physiology Core at JHSOM for training and assistance in the culture of primary mouse enteroids. We acknowledge our funding sources: NIH T32 pre-doctoral training grants to M.P. and B.P. NSF Graduate Research Fellowships to M.P. (DGE-1746891). An NSF CAREER award (MCB-1844994), NIGMS R35 (1R35GM133499), American Cancer Society Research Scholar Grant (133537-RSG-19-005-01-CCG), and Jerome L. Greene Foundation Discovery Award to S.R. M.P. and S.R. conceived the study, analyzed the data, and wrote the manuscript. M.P. and K.R. performed all experiments except nanopore sequencing and intravital imaging. B.P. and W.T. performed nanopore sequence. T.X. and V.G. performed intravital imaging of ERK KTR mice. S.R. supervised the study and secured funding. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = nov,
day = "9",
doi = "10.1016/j.devcel.2020.09.013",
language = "English (US)",
volume = "55",
pages = "328--340.e5",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "3",
}