Publication: Onset of cell differentiation and first lineages decisions in the mouse embryo through the Notch pathway
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2019-01-25
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Abstract
A central question in developmental biology is how a single cell, the zygote, divides and differentiates to generate all the specialised cells that will build a whole organism. The zygote has totipotent capacity, which means that it is able to give rise to any necessary cell type (embryonic or extraembryonic) to form an adult individual. This capacity is gradually reduced during embryonic development, as cells make fate decisions that increase their specialisation at the expense of restricting their developmental potential. The first lineage choice of the mammalian embryo occurs before its implantation in the maternal uterus (so-called preimplantation development) at the blastocyst stage, and leads to the appearance of the first morphologically distinct cell populations: the trophectoderm and the inner cell mass. The trophectoderm is characteristic of mammals and will give rise to extraembryonic tissues such as the placenta, while the inner cell mass will form the embryo proper. Cdx2 is the key gene required for the specification of the trophectoderm and is regulated by the cooperation of two signalling pathways: Hippo and Notch. The Hippo pathway functions as a readout of intracellular polarity cues starting at the morula stage, but little is known about the role of Notch in preimplantation before the blastocyst stage. By using genetic and pharmacological tools in vivo, together with image analysis of single embryos, we have found an early requirement for Notch, which is active from the 4-cell stage, and precedes that of Hippo in the regulation of Cdx2. Moreover, transcriptomic analysis identified novel Notch targets at these stages including early naïve pluripotency markers or transcriptional repressors such as Tle4. Our results unveil a role for Notch in driving the transition towards a more committed state during the gradual loss of potency that takes place in the early mouse embryo prior to the first lineage decisions.