Signaling pathways in mammalian preimplantation development: Linking cellular phenotypes to lineage decisions

Menchero, Sergio; Rayón, Teresa; Andreu, María José; Manzanares, Miguel

doi:10.1002/dvdy.24471

Cited by 30 publications

(27 citation statements)

References 185 publications

(248 reference statements)

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“…Furthermore, only double knockout morulae for Rbpj and Tead4 completely lack CDX2, and all CDX2 positive cells have at least one of the two pathways active. These findings support a model whereby overlapping or complementary inputs from different signalling pathways may provide robustness in the system, buffering any disturbances and ensuring proper development (Menchero et al, 2017). In such a model, Notch and Hippo would ensure the correct specification and maintenance of the TE respectively (Rayon et al, 2014).…”

Section: Discussionsupporting

confidence: 79%

Transitions in cell potency during early mouse development are driven by Notch

Menchero

Rollán

Lopez-Izquierdo

et al. 2019

eLife

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Section: Discussionsupporting

confidence: 79%

Transitions in cell potency during early mouse development are driven by Notch

Menchero

Rollán

Lopez-Izquierdo

et al. 2019

eLife

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“…Furthermore, only double knockout morulae for Rbpj and Tead4 completely lack CDX2, and all CDX2 positive cells have at least one of the two pathways active. These findings support a model whereby overlapping or complementary inputs from different signalling pathways may provide robustness in the system, buffering any disturbances and ensuring proper development [60]. In such a model, Notch and Hippo would ensure the correct specification and maintenance of the TE respectively [16].…”

Section: Discussionsupporting

confidence: 66%

Transitions in cell potency during early mouse development are driven by Notch

Menchero

Lopez-Izquierdo

Rollán

et al. 2018

Preprint

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The Notch signalling pathway plays fundamental roles in diverse developmental processes in metazoans, where it is important in driving cell fate and directing differentiation of various cell types. However, we still have limited knowledge about the role of Notch in early preimplantation stages of mammalian development, or how it interacts with other signalling pathways active at these stages such as Hippo. By using genetic and pharmacological tools in vivo, together with image analysis of single embryos and pluripotent cell culture, we have found that Notch is active from the 4-cell stage. Transcriptomic analysis in single morula identified novel Notch targets, such as early naïve pluripotency markers or transcriptional repressors such as TLE4. Our results reveal a previously undescribed role for Notch in driving transitions during the gradual loss of potency that takes place in the early mouse embryo prior to the first lineage decisions.Menchero et al. 3 IntroductionThe totipotent mammalian zygote has the self-organising capacity of generating embryonic and extraembryonic structures to build a complete organism [1]. This undifferentiated cell will proliferate and its descendants will take lineage decisions that entail a progressive loss of potency. The first differentiation event that leads to distinct lineages takes place during preimplantation development at the morula to blastocyst transition, resulting in the formation of the trophectoderm (TE, extraembryonic population) and the inner cell mass (ICM, embryonic population). How the establishment of these early lineages is achieved has been widely studied and we now know that a combination of morphogenetic cues breaks the symmetry in the embryo [2][3][4]. The first morphological sign of differentiation is evident in the compacting morula, 2.5 days after fertilization (embryonic day E2.5), when blastomeres increase their intercellular interactions and outer cells acquire an apical-basal polarity. These polarized cells on the surface enclose an inner group of apolar cells [5,6]. The outer versus inner position of the blastomeres correlates with their fate, becoming TE or ICM respectively, although cells can change their position within the embryo [7-9]. Prior to compaction, blastomeres appear morphologically equivalent. However, transcriptional differences among blastomeres have been described as early as in the 4-cell embryo [10][11][12]. Although cells at this stage are not committed to a specific fate, these early heterogeneities correlate with specific fate biases before lineage commitment.However, how these early heterogeneities arise and their implications in cell plasticity are still unclear [13].Once the embryo compacts, differences in contractility and the activity of signalling pathways orchestrate the lineage-commitment of cell populations [14][15][16][17][18][19][20]. The initial stochastic expression of the main lineage-specific transcription factors (such as CDX2 or GATA3 for the TE, and OCT4 or NANOG for the ICM) is gradually restricted to their ...

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“…During mouse preimplantation, three cell lineages are produced from two successive differentiation events. The first differentiation between outer and inner cells is essentially driven by the Hippo signalling pathway leading to the production of trophectoderm (TE) and inner cell mass (ICM) cells, respectively (Menchero et al, 2016;Nishioka et al, 2009). During blastocyst formation around embryonic day (E)3.5, epiblast (Epi) and primitive endoderm (PrE) cells appear within the ICM in a 'salt-and-pepper' pattern evidenced by the reciprocal and complementary expression pattern of the transcription factors NANOG and GATA6 (Chazaud et al, 2006;Guo et al, 2010;Kurimoto et al, 2006;Plusa et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the ERK signalling pathway in the developing mouse blastocyst

et al. 2019

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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.

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Signaling pathways in mammalian preimplantation development: Linking cellular phenotypes to lineage decisions

Cited by 30 publications

References 185 publications

Transitions in cell potency during early mouse development are driven by Notch

Transitions in cell potency during early mouse development are driven by Notch

Transitions in cell potency during early mouse development are driven by Notch

Regulation of the ERK signalling pathway in the developing mouse blastocyst

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