Wnt/β-catenin Signaling in Tissue Self-Organization

Abstract

Across metazoans, animal body structures and tissues exist in robust patterns that arise seemingly out of stochasticity of a few early cells in the embryo. These patterns ensure proper tissue form and function during early embryogenesis, development, homeostasis, and regeneration. Fundamental questions are how these patterns are generated and maintained during tissue homeostasis and regeneration. Though fascinating scientists for generations, these ideas remain poorly understood. Today, it is apparent that the Wnt/β-catenin pathway plays a central role in tissue patterning. Wnt proteins are small diffusible morphogens which are essential for cell type specification and patterning of tissues. In this review, we highlight several mechanisms described where the spatial properties of Wnt/β-catenin signaling are controlled, allowing them to work in combination with other diffusible molecules to control tissue patterning. We discuss examples of this self-patterning behavior during development and adult tissues' maintenance. The combination of new physiological culture systems, mathematical approaches, and synthetic biology will continue to fuel discoveries about how tissues are patterned. These insights are critical for understanding the intricate interplay of core patterning signals and how they become disrupted in disease.

Keywords: Wnt; morphogens; reaction-diffusion; self-organization; tissue homeostasis; tissue organization; tissue patterning; β-catenin.

Figure 1

General model for the Wnt/β-catenin signaling pathway and its regulation by the destruction complex. The destruction complex: Axin, Adenomatous polyposis coli (APC), casein kinase 1 α (CK1α), glycogen synthase kinase 3 (GSK3), protein phosphatase 2A (PP2a), and the ubiquitin ligase βTrCP. Membrane receptors: Frizzled (FZD) and low-density lipoprotein receptor-related protein 6 (Lrp6). Dishevelled (Dvl) T-cell factor (TCF).

Figure 2

Wnt/β-catenin signaling in tissue self-organization. Two main categories are shown, Embryogenesis/Development (top) and Regeneration/Homeostasis (bottom). The categories were partitioned due to reversibility. Development of the embryo and body axis as well as appendage development are irreversible and temporally regulated patterning processes. Uniquely, regeneration and homeostasis are ongoing processes that an organism must call upon when needed. These processes have a greater need to be autonomous and could not withstand removal of a morphogen source unless there was a mechanism in place for sensing and replacing a missing niche.

Figure 3

Examples of Wnt/β-catenin-dependent Reaction-Diffusion (RD) mechanisms implicated in tissue patterning. (A) Over time, a short-range activator and a long-range inhibitor interact to form local morphogen concentrations in patterns. (B) Basic model for the RD activator/inhibitor pair. (C) Examples of Wnt-driven patterning driven by RD mechanisms. Although the morphogen pairs/triplets and their mechanisms of control varies, the basic activator/inhibitor concepts are maintained and predicted by mathematical modeling. Patterning images C1–C4 were adapted from References [37,46,47,48].