Mouse neural tube organoids self-organize floorplate through BMP-mediated cluster competition
Teresa Krammer, Hannah T. Stuart, Elena Gromberg, Keisuke Ishihara, Dillon Cislo, Manuela Melchionda, Fernando Becerril Perez, Jingkui Wang, Elena Costantini, Stefanie Lehr, Laura I. Arbanas, Alexandra Hörmann, Ralph A. Neumüller, Nicola Elvassore, Eric D. Siggia, James Briscoe, Anna Kicheva, Elly M. Tanaka
Abstract
During neural tube (NT) development, the notochord induces an organizer, the floorplate, which secretes Sonic Hedgehog (SHH) to pattern neural progenitors. Conversely, NT organoids (NTOs) from embryonic stem cells (ESCs) spontaneously form floorplates without the notochord, demonstrating that stem cells can self-organize without embryonic inducers. Here, we investigated floorplate self-organization in clonal mouse NTOs. Expression of the floorplate marker FOXA2 was initially spatially scattered before resolving into multiple clusters, which underwent competition and sorting, resulting in a stable “winning” floorplate. We identified that BMP signaling governed long-range cluster competition. FOXA2+ clusters expressed BMP4, suppressing FOXA2 in receiving cells while simultaneously expressing the BMP-inhibitor NOGGIN, promoting cluster persistence. Noggin mutation perturbed floorplate formation in NTOs and in the NT in vivo at mid/hindbrain regions, demonstrating how the floorplate can form autonomously without the notochord. Identifying the pathways governing organizer self-organization is critical for harnessing the developmental plasticity of stem cells in tissue engineering.