Progenitors oppositely polarize WNT activators and inhibitors to orchestrate tissue development

Abstract

To spatially co-exist and differentially specify fates within developing tissues, morphogenetic cues must be correctly positioned and interpreted. Here, we investigate mouse hair follicle development to understand how morphogens operate within closely spaced, fate-diverging progenitors. Coupling transcriptomics with genetics, we show that emerging hair progenitors produce both WNTs and WNT inhibitors. Surprisingly, however, instead of generating a negative feedback loop, the signals oppositely polarize, establishing sharp boundaries and consequently a short-range morphogen gradient that we show is essential for three-dimensional pattern formation. By establishing a morphogen gradient at the cellular level, signals become constrained. The progenitor preserves its WNT signaling identity and maintains WNT signaling with underlying mesenchymal neighbors, while its overlying epithelial cells become WNT-restricted. The outcome guarantees emergence of adjacent distinct cell types to pattern the tissue.

Wnt/β-catenin Signaling in Tissue Self-Organization

“…In the past decade, many mechanisms have been discovered by which cells and tissues can propagate morphogen signals by means other than simple free diffusible molecules and Brownian motion. These other mechanisms include transport by motor proteins [ 34 ], mechanical release of tethered molecules [ 35 ], morphogen sequestration/separation [ 36 , 37 ], and handoff by unique cellular structures such as telocytes [ 38 ] or cytonemes [ 39 , 40 , 41 ]. In contrast, activators may be restricted to short distances by chemical modifications or physical boundaries, and this process is known as active diffusion.…”

“…In mammalian models, genetic systems have been used to study Wnt-driven follicle patterning in mice [ 37 ] using a lentiviral in utero delivery method [ 116 ]. Gradients of Wnt have been measured in the small intestine using live imaging of developing organoids and fluorescently tagged Wnt protein [ 63 ], allowing for mapping of Wnt gradients over time and under different genetic conditions.…”

“…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 ].…”

m6A RNA methylation impacts fate choices during skin morphogenesis

“…Notably, immunohistochemistry revealed that in contrast to control HFs, which showed appreciable anti-β-catenin nuclear staining at the follicle: DP interface, in Mettl3 null HFs, β-catenin was mostly at the intercellular borders, reflective of its WNT-independent role at adherens junctions ( Figure 3C). Additionally, these HF progenitors were perturbed in engulfing the DP, a feature seen when WNT-signaling and/or SHH-signaling are inhibited (Heitman et al, 2020;Matos et al, 2020).…”

“…B. Schematic depicting embryonic development of mammalian epithelial skin progenitors. WNT hi/lo implies cells that show strong WNT or low WNT signaling as judged by Axin2-LacZ transgene expression(Matos et al, 2020). HF morphogenesis occurs in temporal waves, with mature HFs emerging shortly after birth.…”