Progenitors oppositely polarize WNT activators and inhibitors to orchestrate tissue development.

Irina Matos,June De La Cruz-Racelis,Laura-Nadine Schuhmacher,Tamara Ouspenskaia,John Levorse,Amma Asare,Elaine Fuchs

doi:10.7554/elife.54304

Irina Matos, June De La Cruz-Racelis + Show 5 more

Open Access

https://doi.org/10.7554/elife.54304

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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.

Highlights

Embryonic development has long fascinated generations of scientists
Sustained activation of WNT disrupts embryonic skin hexagonal patterning. It is well-established that nuclear LEF1 co-localizes with nuclear b-catenin (Fuchs et al, 2001) and with both TOPGAL, a WNT-reporter driven by an enhancer composed of multimerized LEF1 DNA binding sites (DasGupta and Fuchs, 1999), and as shown in Figure 1A, Axin2-LacZ, a WNT-reporter driven by the endogenous WNT target Axin2 (Lustig et al, 2002)
As expected from prior Apc loss of function studies on E14.5 embryos (Kuraguchi et al, 2006), mosaic loss of Apc resulted in overactivation of b-catenin/WNT signaling in patches of transduced skin (Figure 1B)

Summary

Introduction

Embryonic development has long fascinated generations of scientists. Despite years of research, developmental biologists are still puzzled by the remarkable emergence of complex multicellular organisms from single cells. It was proposed that depending upon their local concentration, ‘materials’ form gradients that dictate distinct patterning of otherwise uniform cellular sheets (Boveri, 1901; Morgan, 1901; Dalcq, 1938; Rogers and Schier, 2011). This notion began to crystallize in 1952, when Alan Turing applied mathematical modeling to explain how diffusion of two interacting chemical substances could spontaneously produce a pattern from an homogeneous field of cells (Turing, 1952; Heller and Fuchs, 2015)

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