From Neural Induction in Frogs to Human Brains on Chips

Abstract

The entire nervous system of the vertebrate embryo is derived from an epithelium sheet called the neural plate, which is induced by the organizer/node at the onset of gastrulation. Dissection of the molecular network underlying the emergence of the neural plate, originally performed in Xenopus embryos, led to the discovery of the TGFβ double inhibition mechanism for neural induction, coined ‘the default model’. Years later, these developmental principles have been translated in vitro to instruct human pluripotent stem cells towards neural fate and to build brain organoids. Key Concepts The Spemann organizer is defined by the capability of a group of cells in a transplantation experiment to induce, in a non‐cell‐autonomous fashion, a secondary neural axis and to autonomously differentiate into axial and paraxial mesoderm derivatives. Neural fate acquisition both in vivo in the embryo and in vitro from pluripotent stem cells is the result of blocking the ongoing TGFβ pathway, both Activin‐Nodal and BMP branches. Embryonic stem cells are defined based on two basic properties: their ability to maintain their undifferentiated state (stemness) indefinitely and to be able to differentiate into cell types derived from the three embryonic germ layers (pluripotency). Brain organoids are 3D in vitro structures that resemble several features of the developing human brain. Human pluripotent stem cells cultured in confined geometry (micropattern) self‐organized into defined embryonic structures with standardised cytoarchitecture and distinct cell fates.

Self-organization of human dorsal-ventral forebrain structures by light induced SHH

“…During embryogenesis, the central nervous system (CNS) is derived from an epithelial sheet of cells, the embryonic neural plate, that is induced in a polarized non-cell autonomous manner by a small group of cells called the Spemann organizer (Spemann and Mangold, 1924). Neural induction activity of the organizer occurs by a default mechanism that is exerted through the secretion of soluble inhibitors that block both branches (SMAD1/5/8 and SMAD2/3) of the TGFb signaling pathway (Harland and Gerhart, 1997;Sasai et al, 1994;Brivanlou et al, 1994;Ozair et al, 2013;De Santis and Brivanlou, 2020). Dual SMADs inhibition directly converts pluripotent embryonic stem cells to the anterior neural tissue of the dorso-anterior forebrain (Chambers et al, 2009).…”