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Counter-rotational cell flows drive morphological and cell fate asymmetries in mammalian hair follicles

Nature Cell Biology volume 20, pages 541–552 (2018)Cite this article

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Abstract

Organ morphogenesis is a complex process coordinated by cell specification, epithelial–mesenchymal interactions and tissue polarity. A striking example is the pattern of regularly spaced, globally aligned mammalian hair follicles, which emerges through epidermal-dermal signaling and planar polarized morphogenesis. Here, using live-imaging, we discover that developing hair follicles polarize through dramatic cell rearrangements organized in a counter-rotational pattern of cell flows. Upon hair placode induction, Shh signaling specifies a radial pattern of progenitor fates that, together with planar cell polarity, induce counter-rotational rearrangements through myosin and ROCK-dependent polarized neighbour exchanges. Importantly, these cell rearrangements also establish cell fate asymmetry by repositioning radial progenitors along the anterior–posterior axis. These movements concurrently displace associated mesenchymal cells, which then signal asymmetrically to maintain polarized cell fates. Our results demonstrate how spatial patterning and tissue polarity generate an unexpected collective cell behaviour that in turn, establishes both morphological and cell fate asymmetry.

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Fig. 1: Hair follicle placodes polarize through counter rotational cell flows.
Fig. 2: Polarized shrinkage and growth of intercellular junctions directs cell rearrangements within the placode.
Fig. 3: Counter-rotational cell movements require planar cell polarity.
Fig. 4: Placode polarization and counter rotational movements require Rho kinase and myosin II activity downstream of PCP.
Fig. 5: Planar cell fate asymmetry arises from directional cell rearrangements.
Fig. 6: Asymmetric positioning of the dermal condensate maintains cell fate asymmetry.

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Acknowledgements

We gratefully acknowledge those who provide mouse lines, technical support, and valuable discussions that contributed to this project. We thank Saori Haigo and Jeremy Reiter for generous donation of Vangl2 and Fz6 alleles in mT/mG backgrounds. Michael Deans and Jeremy Nathans kindly provided the Vangl2 and Vangl1 floxed mouse lines. Beniot Aiguoy developed and distributed Packing Analyzer v2 and Tissue Analyzer software for image analysis. We thank Katie Little for assistance with genetic crosses and genotyping, and members of the Devenport lab for insightful comments and suggestions. Finally, we thank Gary Laevsky for imaging support and expertise. The Confocal Facility at Princeton University is a Nikon Center of Excellence. Research reported in this publication was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R01AR066070 and a Vallee Foundation Scholars Award to D.D. L.L. was supported by NIH training grant T32 GM007388.

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Authors and Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Maureen Cetera, Liliya Leybova, Bradley Joyce & Danelle Devenport

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Contributions

Conceptualization, M.C., B.J., and D.D.; Investigation, M.C., L.L., B.J., and D.D..; Writing, M.C., L.L and D.D.; Funding Acquisition and Supervision, D.D.

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Correspondence to Danelle Devenport.

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Integrated supplementary information

Supplementary Figure 1 Cell movements during placode polarization.

(A-D) Spinning disk confocal images from a time series showing placode polarization. Representative placodes from three embryos displaying similar cell movements shown in Figure 1D. Cells express mTomato (magenta) and mGFP driven by K14Cre (green). Mosaicsm allows tracking of small clones through time. See Supplemental Video 3. Coloured dots indicate the same cells through time. The z plane changes in 3μm steps to follow the base of the placode into the dermis. (A) Cells that are initially located at the center of the placode are displaced anteriorly. Supplemental Video 3, left. (B) Cells at the posterior of the placode converge toward the placode midline. Supplemental Video 3, center. (C) Cells at the anterior edge of the placode are displaced laterally and lateral cells are displaced posteriorly. Supplemental Video 3, right. (D) Groups of cells located laterally rotate as cells closest to the center of the placode move anteriorly and cells at the lateral edge move posteriorly. The same placode is used in panels B and D with different groups of cells highlighted. Supplemental Video 3, center. Scale bar, 10μm. Anterior is to the left.

Supplementary Figure 2 Celsr1 polarity in early and polarizing placodes.

Additional examples of Celsr1 asymmetry in early (left) and polarizing placodes (right) representative of 15 measured images from four embryos shown in Figure 2C. The orientation of the line shows the direction of Celsr polarity relative to the AP axis (0 degrees). 0–44 degrees is shown in cyan and 45–90 degrees is shown in yellow. Scale bar, 10μm. Anterior is to the left.

Supplementary Figure 3 Counter-rotational cell flows require planar cell polarity.

Additional example of Fz6 KO placode polarization shown in Figure 3B representative from three embryos. In this example, Fz6 KO cells undergo reduced counter-rotational cell movements, which correlate with the direction of placode growth rather than the AP axis. Spinning disk confocal images from a time series of placode cells expressing mTomato. Cells were segmented and false coloured in a rainbow pattern of vertical lines perpendicular to the direction of growth at the start of the video. Cell tracks show the movement of cells during the designated time window (bottom). Overall cell trajectories are shown in the schematic (right). The z plane changes 3μm in one step to follow the base of the placode into the dermis. Scale bar, 10μm. Anterior is to the left.

Supplementary Figure 4 Placode polarization and counter rotational movements require myosin II and Rho kinase activity.

(A-C) Representative immunofluorescence images of explants cultured from E15.5 in the presence of DMSO (A), blebbistatin (B), and Y-27632 (C) quantified in D. Follicles are labeled with Shh-Cre driving mGFP expression. 1st, 2nd, and 3rd wave follicles are present under all conditions. 1st wave follicles remain polarized in the presence of blebbistatin and Y-27632. Scale bar, 50 µm. (D) Quantification of hair follicle frequencies at each stage after 24 hours in culture. Control, n=649 follicles from 7 embryos and blebbistatin, n=611 follicles from 7 embryos (mean+SD. p= n.s. for all waves control vs blebbistatin, unpaired t-test); control, n=271 follicles from 4 embryos and Y-27632, n=244 follicles from 4 embryos (mean+SD. p= n.s. for all waves control vs. Y-27632). (E) Additional representative placode shown in Figure 4E from five treated explants. Y-27632 inhibits counter-rotational cell flows. Spinning disk confocal images from a 13.3 hour time series of placode cells expressing mTomato (top). Cells were segmented and false coloured in a rainbow pattern of vertical lines perpendicular to the AP axis at the beginning of the video. Cell tracks show the movement of cells during the designated time window (bottom). Overall cell trajectories are shown in the schematic (right). Cells remain in their original rainbow pattern. Scale bar, 10μm. Anterior is to the left.

Supplementary Figure 5 Characterization of placode morphology and cell movements in Shh mutants.

(A-C) Shh KO embryos display expanded and irregular shaped placodes. (A) In controls, Shh-GFP (green) and P-Cadherin (magenta) mark the inner placode. In Shh KO embryos, the zone of Shh-GFP and P-Cadherin is expanded, irregularly shaped, and lacks a smooth boundary between GFP+ and GFP- cells. Representative mild and severe Shh KO examples along with a control, quantified in B. (B) Quantification of placode morphologies. The area and perimeter of Shh KO placodes, as measured by the zone of Shh-GFP expression, are expanded compared to controls. Shh KO placodes are less circular and more anisotropic than controls. n=30 control placodes from 3 embryos; n= 40 ShhKO placodes from 4 embryos. Lines show mean+SD. p=1.25x10−16 for area, p=1.06x10−16 for perimeter, p= 8.82x10−7 for circularity, p= 8.78x10−7 for aspect ratio, two-tailed t-tests with Welch’s correction for unequal variances (except for aspect ratio, where variances are not significantly different). (C) Shh-Cre>mGFP highlights the irregular morphology and poor compartmentalization of Shh KO placodes. E15.5 explants were cultured overnight before fixation. Representative images from two control and two mutant embryos. (D) Shh KO placode cells undergo atypical cell rearrangements. Additional example to Figure 5C. Spinning disk confocal images from a time series of placode cells expressing mTomato (top). Cells were segmented and false coloured in a rainbow pattern of vertical lines perpendicular to the AP axis at the beginning of the video. Cell tracks show the movement of cells during the designated time window (bottom). Additional placode representative of two embryos. Overall cell trajectories are shown in the schematic (right). Scale bar, 10μm. Anterior is to the left.

Supplementary Figure 6 Cell fate asymmetry requires myosin II and Rho kinase activity.

Shh-Cre driving mGFP marks anterior placode cell fates (green) while Sox9 marks posterior placode cell fates (magenta). Representative immunofluorescence images of germ placodes cultured from E15.5 in the presence of DMSO (left), blebbistatin (center), and Y-27632 (right) quantified in Figure S4D. Shh and Sox9 expressing cells fail to separate along the AP axis in the presence of myosin or Rho kinase inhibitors. Scale bar, 10µm. Anterior is to the left.

Supplementary information

Supplementary Information

Supplementary Figures 1–6, Supplementary Table and Video legends

Reporting Summary

Supplementary Table 1

Mouse genotypes.

Supplementary Table 2

Statistics source data.

Supplementary Video 1

Live imaging of embryonic skin development.

Supplementary Video 2

Live imaging of hair placode polarization.

Supplementary Video 3

Region specific cell movements during placode polarization.

Supplementary Video 4

Live imaging of tracked cells during placode polarization shows counter-rotational cell movements.

Supplementary Video 5

Counter-rotational cell movements fail to occur in Vangl mutants.

Supplementary Video 6

Counter-rotational cell movements occur in the direction of placode growth in Fz6 mutants.

Supplementary Video 7

Rho kinase inhibitor blocks counter-rotational cell movements in mid-polarizing placodes.

Supplementary Video 8

Shh mutant placodes undergo extensive cell rearrangements.

Supplementary Video 9

Counter-rotational cell flows within the placode polarize the dermal condensate.

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Cetera, M., Leybova, L., Joyce, B. et al. Counter-rotational cell flows drive morphological and cell fate asymmetries in mammalian hair follicles. Nat Cell Biol 20, 541–552 (2018). https://doi.org/10.1038/s41556-018-0082-7

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