Establishing the effect of morphogens at the supracellular scale during organ formation - PROJECT SUMMARY/ABSTRACT A major challenge in understanding how organs take shape is addressing how increases in morphological complexity arise. Over the past half-century, our understanding of such symmetry-breaking has been predominantly developed through molecular, genetic, and cellular frameworks. However, symmetry-breaking in developing organs occurs at scales far larger than their individual molecular and cellular constituents, prompting the question of how events at the molecular and cellular scale relate to the physical self-organization of organ structure. To address this question, my lab centers its studies on the behavior of cell collectives, an understudied nexus that serves as a mediator between subcellular processes and functionally relevant organ morphology. Our prior work in considering collective cell, or supracellular, material properties has led to the hypothesis that the role of key signals, known as morphogens, in sculpting organs is to influence cells and extracellular matrix such that tissue material properties or “phase” are modulated. Thus, a key functional role of morphogens may be to create diversity in supracellular mechanical behavior by fluidizing or solidifying tissue domains that result in the increase of complexity in organ form. Here we will use a unique set of supracellular behavioral assays to investigate new roles for signals in shaping emerging morphologies. We will first link where and when morphogens are expressed in the forming follicle to the transcriptional profiles and multicellular architectures that accompany morphogen activity (Aim 1). We will then leverage a constellation of novel collective cell mechanics platforms to probe the functional consequence of morphogen activity at the supracellular scale. (Aim 2). Finally, through the integration of theory and experiment, we will explore the hypothesis that interacting supracellular phases generate a mechanical instability in the skin that is sufficient to shape the organ (Aim 3). Together these studies stand to highlight the need to consider supracellular properties necessary for tissue symmetry breaking that are not reducible to the properties of individual cells. At the same time, our studies will identify the molecular and cellular component parts that enable the diversification of emergent supracellular material properties. Our investigations will pave the way for a generalizable paradigm for how morphogens can create adjacent material phases within a single tissue, thereby generating the potential for mechanical self- organization at the tissue scale. Finally, these studies will shed light on the multi-scale nature of organ formation and serve as a foundation for future work aimed at addressing congenital defects, engineering stromal tissues of specific material properties, and the rational channeling supracellular self-organizing potential in regenerative medicine.
