Self-organization of a human organizer by combined Wnt and Nodal signalling

Nature. 2018 Jun;558(7708):132-135. doi: 10.1038/s41586-018-0150-y. Epub 2018 May 23.

Abstract

In amniotes, the development of the primitive streak and its accompanying 'organizer' define the first stages of gastrulation. Although these structures have been characterized in detail in model organisms, the human primitive streak and organizer remain a mystery. When stimulated with BMP4, micropatterned colonies of human embryonic stem cells self-organize to generate early embryonic germ layers 1 . Here we show that, in the same type of colonies, Wnt signalling is sufficient to induce a primitive streak, and stimulation with Wnt and Activin is sufficient to induce an organizer, as characterized by embryo-like sharp boundary formation, markers of epithelial-to-mesenchymal transition and expression of the organizer-specific transcription factor GSC. Moreover, when grafted into chick embryos, human stem cell colonies treated with Wnt and Activin induce and contribute autonomously to a secondary axis while inducing a neural fate in the host. This fulfils the most stringent functional criteria for an organizer, and its discovery represents a milestone in human embryology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activins / metabolism
  • Animals
  • Bone Morphogenetic Protein 4 / metabolism
  • Cell Line
  • Chick Embryo
  • Epithelial-Mesenchymal Transition
  • Goosecoid Protein / metabolism
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Mice
  • Nerve Tissue / cytology
  • Nerve Tissue / embryology
  • Nerve Tissue / metabolism
  • Nodal Protein / metabolism*
  • Organizers, Embryonic / cytology
  • Organizers, Embryonic / embryology*
  • Organizers, Embryonic / metabolism*
  • Primitive Streak / cytology
  • Primitive Streak / metabolism
  • Wnt Proteins / metabolism*
  • Wnt Signaling Pathway*

Substances

  • BMP4 protein, human
  • Bone Morphogenetic Protein 4
  • GSC protein, human
  • Goosecoid Protein
  • NODAL protein, human
  • Nodal Protein
  • Wnt Proteins
  • Activins