RESUMEN
Activation of the ERK signalling pathway is essential for the differentiation of the inner cell mass (ICM) during mouse preimplantation development. We show here that ERK phosphorylation occurs in ICM precursor cells, in differentiated primitive endoderm (PrE) cells as well as in the mature, formative state epiblast (Epi). We further show that DUSP4 and ETV5, factors often involved in negative-feedback loops of the FGF pathway, are differently regulated. Whereas DUSP4 presence clearly depends on ERK phosphorylation in PrE cells, ETV5 localises mainly to Epi cells. Unexpectedly, ETV5 accumulation does not depend on direct activation by ERK but requires NANOG activity. Indeed ETV5, like Fgf4 expression, is not present in Nanog mutant embryos. Our results lead us to propose that in pluripotent early Epi cells, NANOG induces the expression of both Fgf4 and Etv5 to enable the differentiation of neighbouring cells into the PrE while protecting the Epi identity from autocrine signalling.
Asunto(s)
Blastocisto/metabolismo , Desarrollo Embrionario/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Sistema de Señalización de MAP Quinasas , Animales , Masa Celular Interna del Blastocisto/citología , Masa Celular Interna del Blastocisto/fisiología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Factor 4 de Crecimiento de Fibroblastos/genética , Factor 4 de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Sistema de Señalización de MAP Quinasas/genética , Ratones , Ratones Endogámicos ICR , Ratones Transgénicos , Proteína Homeótica Nanog/genética , Proteína Homeótica Nanog/metabolismo , Proteínas Tirosina Fosfatasas/fisiología , Transducción de Señal/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
At the time of implantation, the mouse blastocyst has developed three cell lineages: the epiblast (Epi), the primitive endoderm (PrE), and the trophectoderm (TE). The PrE and TE are extraembryonic tissues but their interactions with the Epi are critical to sustain embryonic growth, as well as to pattern the embryo. We review here the cellular and molecular events that lead to the production of PrE and Epi lineages and discuss the different hypotheses that are proposed for the induction of these cell types. In the second part, we report the current knowledge about the epithelialization of the PrE.
Asunto(s)
Tipificación del Cuerpo , Diferenciación Celular , Endodermo/citología , Epitelio/embriología , Animales , Blastocisto/citología , Estratos Germinativos/citología , Estratos Germinativos/embriología , HumanosRESUMEN
Known molecular determinants of developmental plasticity are mainly transcription factors, while the extrinsic regulation of this process has been largely unexplored. Here we identify Cripto as one of the earliest epiblast markers and a key extracellular determinant of the naive and primed pluripotent states. We demonstrate that Cripto sustains mouse embryonic stem cell (ESC) self-renewal by modulating Wnt/ß-catenin, whereas it maintains mouse epiblast stem cell (EpiSC) and human ESC pluripotency through Nodal/Smad2. Moreover, we provide unprecedented evidence that Cripto controls the metabolic reprogramming in ESCs to EpiSC transition. Remarkably, Cripto deficiency attenuates ESC lineage restriction in vitro and in vivo, and permits ESC transdifferentiation into trophectoderm lineage, suggesting that Cripto has earlier functions than previously recognized. All together, our studies provide novel insights into the current model of mammalian pluripotency and contribute to the understanding of the extrinsic regulation of the first cell lineage decision in the embryo.