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The primitive endoderm supports lineage plasticity to enable regulative development [RNA-seq]

ABSTRACT: Mammalian blastocyst formation involves the sequential specification of trophectoderm and the differentiation of inner cell mass into either epiblast or primitive endoderm. During this time, the embryo maintains a window of plasticity and able to redirect its cellular fate when challenged experimentally. In this context, we found that the primitive endoderm alone was capable of regenerating a complete blastocyst and continue normal postimplantation development. We identify an in vitro population similar to the early primitive endoderm in vivo that exhibits plasticity, forms three dimensional embryoid structures and exhibits multilineage competence in chimera assays. Here, we find OCT4 as the main player in collaborating with endodermal transcription factors to maintain pluripotent enhancers in a state that is primed for activation mediated by JAK/STAT signalling. Our observations support the notion that transcription factor persistence underlies plasticity in regulative development and highlights the importance of primitive endoderm in perturbed development.

ORGANISM(S): Mus musculus

PROVIDER: GSE232921 | GEO | 2024/06/25

REPOSITORIES: GEO

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Project description:p38-MAPKs are stress activated kinases necessary for placental development and nutrient and oxygen transfer during murine post-implantation development. In preimplantation development, p38-MAPK activity is required for blastocyst formation. Additionally, we have previously reported its role in regulating specification of inner cell mass (ICM) towards primitive endoderm (PrE), although a comprehensive mechanistic understanding is currently limited. Adopting live embryo imaging, proteomic and transcriptomic approaches, we report experimental data that directly address this deficit. Chemical inhibition of p38-MAPK activity during blastocyst maturation causes impaired blastocyst cavity expansion, most evident between the third and tenth hours post inhibition onset. We identify an overlapping minimal early blastocyst maturation window of p38-MAPKi inhibition (p38-MAPKi) sensitivity, that is sufficient to impair PrE cell fate by the late blastocyst (E4.5) stage. Comparative proteomic analyses reveal substantial downregulation of ribosomal proteins, the mRNA transcripts of which are also significantly upregulated. Ontological analysis of the differentially expressed transcriptome during this developmental period reveals “translation” related gene transcripts as being most significantly, yet transiently, affected by p38-MAPKi. Moreover, combined assays consistently report concomitant reductions in de novo translation that are associated with accumulation of unprocessed rRNA precursors. Using a phospho-proteomic approach, ± p38-MAPKi, to potentially identify p38-MAPK effectors, we report that clonal siRNA mediated knockdown of Mybpp1a, an rRNA transcription and processing regulator gene, is associated with significantly diminished PrE contribution. Lastly, we show that defective PrE specification caused by p38-MAPKi (but not MEK/ERK signalling inhibition) can be partially rescued by activating the archetypal mTOR mediated translation regulatory pathway. Activated p38-MAPK controls blastocyst maturation in an early and distinctly transient developmental window by regulating gene functionalities related to translation, that creates a permissive environment for appropriate specification of ICM cell fate.

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The primitive endoderm supports lineage plasticity to enable regulative development [RNA-seq]

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