Morphogen Gradients as Drivers of Mosaicism During Early Human Development

WNT, BMP, FGF, and Nodal signalling gradients drive naive to primed epiblast transitions and primitive endoderm specification, as well as subsequent gastrulation of the implanted embryo. Recently, these pathways were shown to control a signalling rheostat that modulates chromosome replication and segregation fidelity in human pluripotent stem cells. In particular, WNT and BMP antagonists associated with embryo anteriorization during gastrulation (DKK1, Cerberus, LEFTY2, Noggin, and Chordin) induce DNA replication stress and damage in S-phase leading to ultra-fine-bridges and whole-chromosome mis segregation in the subsequent mitosis. Of note, aneuploidy in pre- and early post-implantation embryos is the first cause of miscarriage in humans, and has also been associated with neurodevelopmental disorders. Here, we hypothesize that the antero-posterior (A-P) signalling gradient generates overlapping patterns of genome and chromosomal mosaicism in human embryos, with potential links to human infertility and lineage-specific developmental disorders.