Interplay between Morphogen Signaling and Tissue Geometry in Early Mammalian Development

Abstract

Morphogens are long-range signals that induce concentration-dependent responses across developing tissues, directing the patterning and morphogenesis of embryos. Though multiple morphogens have been identified, characterized, and shown to be essential for development, it is often unclear how morphogens move through a complex and dynamic environment within the embryo to establish reliable concentration gradients. Further, little is known about how these gradients are interpreted by progenitor tissues, particularly in mammalian embryos where experimental access is challenging. In this dissertation supervised by Sharad Ramanathan, I, together with Zhechun Zhang, show that formation of a robust BMP signaling gradient in the early mouse embryo is dependent upon the geometric compartmentalization of the embryo and the basolateral localization of BMP receptors, which restricts where BMP morphogens are sensed in vivo. With evidence from mathematical modeling, human embryonic stem cells in vitro, and mouse embryos in vivo, we demonstrate that this mechanism organizes morphogen signaling gradients in epithelial tissues that are buffered against fluctuations. I also describe preliminary work with Tianlei He developing methods to control the spatiotemporal and combinatorial presentation of morphogens to human organoids in vitro, via the precise, rapid deposition of hundreds of morphogen-soaked beads and organoids on a single chip. I conclude by discussing how this approach can be used to interrogate the nature of morphogen interpretation in human tissues at the quantitative scale necessary to understand its complexities.