Amnion signals are essential for mesoderm formation in primates

Embryonic development is largely conserved among mammals. However, certain genes show divergent functions. By generating a transcriptional atlas containing >30,000 cells from post-implantation non-human primate embryos, we uncover that ISL1, a gene with a well-established role in cardiogenesis, controls a gene regulatory network in primate amnion. CRISPR/Cas9-targeting of ISL1 results in non-human primate embryos which do not yield viable offspring, demonstrating that ISL1 is critically required in primate embryogenesis. On a cellular level, mutant ISL1 embryos display a failure in mesoderm formation due to reduced BMP4 signaling from the amnion. Via loss of function and rescue studies in human embryonic stem cells we confirm a similar role of ISL1 in human in vitro derived amnion. This study highlights the importance of the amnion as a signaling center during primate mesoderm formation and demonstrates the potential of in vitro primate model systems to dissect the genetics of early human embryonic development. Overall design: Single cell gene expression profiling (mRNA) of in vitro cultured wildtype and ISL1 hypomorphic mutant cynomologus monkey embryos at Day 10, Day 12 and Day 14. WT-batch 1: D10 2 embryos, D12 1 embryo, D14 2 embyos; WT-batch 2: D10 3 embryos, D12 2 embryos, D14 2 embryos; ISL1-mutant batch-1: D10 3 embryos, D12 3 embryos, D14 3 embryos; ISL1-mutant batch-2: D12 1 embryo, D14 1 embryo