Live Visualization of ERK Activity in the Mouse Blastocyst Reveals Lineage-Specific Signaling Dynamics

Simon, Claire; Rahman, Shahadat; Raina, Dhruv; Schröter, Christian; Hadjantonakis, Anna‐Katerina

doi:10.1016/j.devcel.2020.09.030

Cited by 72 publications

(92 citation statements)

References 90 publications

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“…Although we observed low-level Spry4 H2BVenus expression within PGCs and PGCLCs, indicating that MAPK signaling may not be entirely shut down, this could also represent perdurance of the Venus reporter. Therefore, future studies using dynamic ERK biosensors [46, 47], combined with time-lapse imaging [48], will uncover precise signaling dynamics. We also observed that the MAPK response was elevated in PGCs within the hindgut endoderm, consistent with studies showing that FGF plays a role in germ cell migration [45, 49].…”

Section: Discussionmentioning

confidence: 99%

Quantitative analysis of signaling responses during mouse primordial germ cell specification

Morgani

Hadjantonakis

2021

Preprint

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During early mammalian development, the pluripotent cells of the embryo are exposed to a combination of signals that drive exit from pluripotency and germ layer differentiation. At the same time, a small population of pluripotent cells give rise to the primordial germ cells (PGCs), the precursors of the sperm and egg, which pass on heritable genetic information to the next generation. Despite the importance of PGCs, it remains unclear how they are first segregated from the soma, and if this involves distinct responses to their signaling environment. To investigate this question, we mapped BMP, MAPK and WNT signaling responses over time in PGCs and their surrounding niche in vitro and in vivo at single-cell resolution. We showed that, in the mouse embryo, early PGCs exhibit lower BMP and MAPK responses compared to neighboring extraembryonic mesoderm cells, suggesting the emergence of distinct signaling regulatory mechanisms in the germline versus soma. In contrast, PGCs and somatic cells responded comparably to WNT, indicating that this signal alone is not sufficient to promote somatic differentiation. Finally, we investigated the requirement of a BMP response for these cell fate decisions. We found that cell lines with a mutation in the BMP receptor (Bmpr1a−/−), which exhibit an impaired BMP signaling response, can efficiently generate PGC-like cells revealing that canonical BMP signaling is not cell autonomously required to direct PGC-like differentiation.

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Section: Discussionmentioning

confidence: 99%

Quantitative analysis of signaling responses during mouse primordial germ cell specification

Morgani

Hadjantonakis

2021

Preprint

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“…A high ERK activity is found throughout all stages of murine preimplantation development, and only during blastocyst formation a transient ERK inhibition in a subset of cells was found, supporting reports that suggested a low ERK activity resulting in EPI specification, while high ERK activity induces PE formation. This transient ERK inactivation indicates a coordination of cell cycle, signaling and differentiation during embryo formation [ 168 , 169 ]. Another pathway, which plays a vital role in maintaining pluripotency is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway.…”

Section: New Insights Into Preimplantation Development From Alternative Model Organismsmentioning

confidence: 99%

A New Toolbox in Experimental Embryology—Alternative Model Organisms for Studying Preimplantation Development

Springer

Wolf

Simmet

2021

JDB

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Preimplantation development is well conserved across mammalian species, but major differences in developmental kinetics, regulation of early lineage differentiation and implantation require studies in different model organisms, especially to better understand human development. Large domestic species, such as cattle and pig, resemble human development in many different aspects, i.e., the timing of zygotic genome activation, mechanisms of early lineage differentiations and the period until blastocyst formation. In this article, we give an overview of different assisted reproductive technologies, which are well established in cattle and pig and make them easily accessible to study early embryonic development. We outline the available technologies to create genetically modified models and to modulate lineage differentiation as well as recent methodological developments in genome sequencing and imaging, which form an immense toolbox for research. Finally, we compare the most recent findings in regulation of the first lineage differentiations across species and show how alternative models enhance our understanding of preimplantation development.

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“…Examples include the signaling pulses observed from the tumor suppressor p53, the mitogen associated protein kinase (MAPK) Erk, and the immune signaling transcription factor NF-κB [1][2][3][4][5] . Pulses of Erk activity have been observed in vivo in the early mouse embryo 6,7 and in 53 tumors 8 , and self-organize into propagating waves from sites of epithelial injury in both mouse 9 54 and zebrafish 10 . The breadth of biological systems exhibiting signaling dynamics suggests that they may play important functional roles.…”

Section: Main Textmentioning

confidence: 99%

A synthetic gene circuit for imaging-free detection of dynamic cell signaling

Ravindran

McFann

Toettcher

2021

Preprint

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Cells employ intracellular signaling pathways to sense and respond to changes in their external environment. In recent years, live-cell biosensors have revealed complex pulsatile dynamics in many pathways, but studies of these signaling dynamics are limited by the necessity of live-cell imaging at high spatiotemporal resolution1. Here, we describe an approach to infer pulsatile signaling dynamics from just a single measurement in fixed cells using a pulse-detecting gene circuit. We computationally screened for circuit with pulse detecting capability, revealing an incoherent feedforward topology that robustly performs this computation. We then implemented the motif experimentally for the Erk signaling pathway using a single engineered transcription factor and fluorescent protein reporter. Our ‘recorder of Erk activity dynamics’ (READer) responds sensitively to both spontaneous and stimulus-driven Erk pulses. READer circuits thus open the door to permanently labeling transient, dynamic cell populations to elucidate the mechanistic underpinnings and biological consequences of signaling dynamics.

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Live Visualization of ERK Activity in the Mouse Blastocyst Reveals Lineage-Specific Signaling Dynamics

Cited by 72 publications

References 90 publications

Quantitative analysis of signaling responses during mouse primordial germ cell specification

Quantitative analysis of signaling responses during mouse primordial germ cell specification

A New Toolbox in Experimental Embryology—Alternative Model Organisms for Studying Preimplantation Development

A synthetic gene circuit for imaging-free detection of dynamic cell signaling

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