Cell-to-cell expression variability followed by signal reinforcement progressively segregates early mouse lineages

Abstract

It is now recognized that extensive expression heterogeneities among cells precede the emergence of lineages in the early mammalian embryo. To establish a map of pluripotent epiblast (EPI) versus primitive endoderm (PrE) lineage segregation within the inner cell mass (ICM) of the mouse blastocyst, we characterised the gene expression profiles of individual ICM cells. Clustering analysis of the transcriptomes of 66 cells demonstrated that initially they are non-distinguishable. Early in the segregation, lineage-specific marker expression exhibited no apparent correlation, and a hierarchical relationship was established only in the late blastocyst. Fgf4 exhibited a bimodal expression at the earliest stage analysed, and in its absence, the differentiation of PrE and EPI was halted, indicating that Fgf4 drives, and is required for, ICM lineage segregation. These data lead us to propose a model where stochastic cell-to-cell expression heterogeneity followed by signal reinforcement underlies ICM lineage segregation by antagonistically separating equivalent cells.

A strategy for tissue self-organization that is robust to cellular heterogeneity and plasticity

“…During development, changes to this balance of interactions can be used to drive tissue rearrangements and morphogenesis (28). In adult tissues, however, disrupting this balance of interactions would disrupt the capacity of multiple populations of cells to retain a single correct multicellular architecture in the absence of other mechanisms of control.…”

Unequal distribution of 16S mtrRNA at the 2-cell stage regulates cell lineage allocations in mouse embryos

“…This suggests that 16S mtrRNA may participate in the regulation of cell allocations prior to cell lineage specific gene expression (Nance 2014, Rayon et al 2014. Recent genome-wide gene expression analyses on early embryonic cells in both mouse and C. elegans indicated a bi-facet model of cell lineage determination, in which an earlier stochastic heterogeneous geneexpression stage when cells appear non-distinguishable is followed by a late reinforced homogeneous geneexpression stage when cells gain respective molecular signatures (Ohnishi et al 2014, Du et al 2015. These suggested that perhaps earlier events preluding more definitive cell-lineage determination pathways are regulated by post-transcriptional mechanisms, involving various RNA species and RNA binding proteins.…”

Le rôle des phénomènes aléatoires dans le cancer

“…Ces données nous permettent de renouveler notre vision de l'origine et du rôle des cellules souches cancéreuses. Il faut d'abord relever que si les cellules souches embryonnaires expriment leur génome de manière très aléatoire et généralisée in vitro [14] comme in vivo [22], la structuration tissulaire est au contraire marquée par une diminution de la stochasticité de l'expression des gènes [23,24]. La pluripotence des cellules souches serait le fruit d'un état d'instabilité intrinsèque de l'expression des gènes, responsable lui-même du grand nombre de voies développementales possibles pour ces cellules.…”

“…Ce schéma est en accord avec la théorie de l'ontophylogenèse développée par Jean-Jacques Kupiec [26,32] (➜) : selon celle-ci, la stochasticité de l'expression des gènes au sein des cellules indiffé-renciées permet un processus sélec-tif au niveau cellulaire aboutissant à la stabilisation de l'expression d'un panel de gènes adaptés à un environnement donné grâce aux interactions établies par la cellule avec cet environnement. Ce processus en deux phases, en particulier le rôle de la signalisation cellulaire issue des interactions cellulaires dans la phase de stabilisation de l'expression génique au cours du développement, a été confirmé expérimentalement [23].…”