Position- and Hippo signaling-dependent plasticityduring lineage segregation in the early mouse embryo
- Hospital for Sick Children, Canada
- Karolinska Institutet, Sweden
- University Health Network, Canada
Abstract
The segregation of the trophectoderm (TE) from the inner cell mass (ICM) in the mouse blastocyst is determined by position-dependent Hippo signaling. However, the window of responsiveness to Hippo signaling, the exact timing of lineage commitment and the overall relationship between cell commitment and global gene expression changes are still unclear. Single-cell RNA sequencing during lineage segregation revealed that the TE transcriptional profile stabilizes earlier than the ICM and prior to blastocyst formation. Using quantitative Cdx2-eGFP expression as a readout of Hippo signaling activity, we assessed the experimental potential of individual blastomeres based on their level of Cdx2-eGFP expression and correlated potential with gene expression dynamics. We find that TE specification and commitment coincide and occur at the time of transcriptional stabilization, whereas ICM cells still retain the ability to regenerate TE up to the early blastocyst stage. Plasticity of both lineages is coincident with their window of sensitivity to Hippo signaling.
Data availability
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Sequential loss of plasticity during trophectoderm and inner cell mass lineage segregation in the mouse embryoPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE84892).
Article and author information
Author details
Funding
Canadian Institutes of Health Research (FDN-143334)
- Janet Rossant
Ragnar Söderbergs stiftelse (M67/13)
- Fredrik Lanner
Swedish Foundation for Strategic Research (ICA12-0001)
- Fredrik Lanner
Knut och Alice Wallenbergs Stiftelse (2015.0096)
- Fredrik Lanner
Swedish Research Council (2013-2570)
- Fredrik Lanner
Restracomp fellowship (post-doctoral fellowship)
- Eszter Posfai
Mats Sundin Fellowship (post-doctoral fellowship)
- Sophie Petropoulos
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal work was carried out following Canadian Council on Animal Care Guidelines for Use of Animals in Research and Laboratory Animal Care under protocols (protocol number: 20-0026H) approved by The Centre for Phenogenomics Animal Care Committee.
Copyright
© 2017, Posfai et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Position- and Hippo signaling-dependent plasticityduring lineage segregation in the early mouse embryo
eLife 6:e22906.
https://doi.org/10.7554/eLife.22906
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The evolutionarily conserved Hippo (Hpo) pathway has been shown to impact early development and tumorigenesis by governing cell proliferation and apoptosis. However, its post-developmental roles are relatively unexplored. Here, we demonstrate its roles in post-mitotic cells by showing that defective Hpo signaling accelerates age-associated structural and functional decline of neurons in Caenorhabditis elegans. Loss of wts-1/LATS, the core kinase of the Hpo pathway, resulted in premature deformation of touch neurons and impaired touch responses in a yap-1/YAP-dependent manner, the downstream transcriptional co-activator of LATS. Decreased movement as well as microtubule destabilization by treatment with colchicine or disruption of microtubule-stabilizing genes alleviated the neuronal deformation of wts-1 mutants. Colchicine exerted neuroprotective effects even during normal aging. In addition, the deficiency of a microtubule-severing enzyme spas-1 also led to precocious structural deformation. These results consistently suggest that hyper-stabilized microtubules in both wts-1-deficient neurons and normally aged neurons are detrimental to the maintenance of neuronal structural integrity. In summary, Hpo pathway governs the structural and functional maintenance of differentiated neurons by modulating microtubule stability, raising the possibility that the microtubule stability of fully developed neurons could be a promising target to delay neuronal aging. Our study provides potential therapeutic approaches to combat age- or disease-related neurodegeneration.
