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Self-organization of a functional human organizer by combined WNT and NODAL signalling

By I. Martyn, T.Y. Kanno, A. Ruzo, E.D. Siggia, A.H. Brivanlou

Posted 15 Dec 2017
bioRxiv DOI: 10.1101/234633 (published DOI: 10.1038/s41586-018-0150-y)

In amniotes, the development of the primitive streak (PS) and its accompanying 'organizer' define the first stages of gastrulation. Despite detailed characterization in model organisms, the analogous human structures remain a mystery. We have previously shown that when stimulated with BMP4, micropatterned colonies of human embryonic stem cells (hESCs) self-organize to generate early embryonic germ layers1. Here we show that in the same type of colonies WNT signalling is sufficient to induce a PS, and WNT with ACTIVIN is sufficient to induce an organizer, as characterized by embryo-like sharp boundary formation, epithelial-to-mesenchymal transition (EMT) markers, and expression of the organizer specific transcription factor GSC. Moreover, when grafted into chick embryos, WNT and ACTIVIN treated human cells induce and contribute autonomously to a secondary axis while inducing neural fate in the host. This fulfills the most stringent functional criteria for an organizer, and its discovery represents a major milestone in human embryology.

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