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. 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