Recapitulating and Understanding Human Embryonic Axial Elongation and Neurulation

Abstract

Embryonic development is a complex interplay between intercellular signaling, intracellular gene expression dynamics, and multicellular rearrangements. How cells in the embryo choose their fates and structure themselves into tissues and organs is a central question in developmental biology. The recent derivation of human pluripotent stem cells has enabled the study of human embryonic development in vitro. However, stem cell differentiation is prone to variability in contrast to the robustness of the embryo. In this thesis, I combine approaches from engineering and statistical learning with insights from developmental biology to reproducibly direct the axial symmetry breaking of embryonic organoids derived from human pluripotent stem cells (Chapter 2). I use this approach to recapitulate anteroposterior elongation (Chapter 3) and mediolateral folding (Chapter 4) of the neural tube. Using chemical and genetic perturbations, single cell methods, and microscopy, I investigate the molecular and cellular mechanisms underlying these morphogenetic processes. An extension of these approaches could provide deeper understanding of the root causes of human developmental disorders.