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Developmental mechanisms of stripe patterns in rodents

Abstract

Mammalian colour patterns are among the most recognizable characteristics found in nature and can have a profound impact on fitness. However, little is known about the mechanisms underlying the formation and subsequent evolution of these patterns. Here we show that, in the African striped mouse (Rhabdomys pumilio), periodic dorsal stripes result from underlying differences in melanocyte maturation, which give rise to spatial variation in hair colour. We identify the transcription factor ALX3 as a regulator of this process. In embryonic dorsal skin, patterned expression of Alx3 precedes pigment stripes and acts to directly repress Mitf, a master regulator of melanocyte differentiation, thereby giving rise to light-coloured hair. Moreover, Alx3 is upregulated in the light stripes of chipmunks, which have independently evolved a similar dorsal pattern. Our results show a previously undescribed mechanism for modulating spatial variation in hair colour and provide insights into how phenotypic novelty evolves.

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Figure 1: Phenotypic characterization.
Figure 2: Alx3 is a candidate for regulating spatial differences in hair colour.
Figure 3: Alx3 decreases melanin synthesis in vivo.
Figure 4: Alx3 binds to the Mitf promoter directly.
Figure 5: Hair colour patterning mechanisms in rodents.

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Acknowledgements

We thank D. Mishkind, M. Omura, J. Chupasko, P. Walsh, T. Capellini, T. Linden, K. Turner and N. Hughes for providing technical and logistical support, and C. Perdomo, A. Bendesky, C. K. Hu, D. M. Kingsley and J. M. Lassance for discussions. M.Mi. and M.V. are supported by the Spanish Ministry of Economy and Competitiveness (MINECO grants BFU2011-24245 and BFU2014-52149-R) and Instituto de Salud Carlos III. CIBERDEM is an initiative of the Instituto de Salud Carlos III. H.E.H. is an Investigator of the Howard Hughes Medical Institute.

Author information

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Authors

Contributions

R.M., M.Ma. and H.E.H. conceived the project. R.M., G.S.B. and H.E.H. designed experiments. R.M. performed cell proliferation assays, immunohistochemistry, quantitative PCR, in situ hybridizations, comparative sequence analysis, in vitro gain- and loss-of-function experiments and luciferase reporter assays. R.M. and M.Ma. collected samples and performed phenotypic characterization; R.M. and S.B. performed in vivo ultrasound-guided lentiviral injections. C.H. carried out the large-scale RNA experiments, including construction and annotation of the de novo transcriptome, and design and analysis of the RNA-seq work. M.Mi. and M.V. performed protein–DNA binding assays. C.S. provided the first embryos for pilot studies and founding members for the striped mice laboratory colony. R.M., G.S.B. and H.E.H. wrote the paper with input from all authors.

Corresponding author

Correspondence to Hopi E. Hoekstra.

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Competing interests

The authors declare no competing financial interests.

Additional information

Reviewer Information Nature thanks H. Arnheiter, T. Caro, M. Levine and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data figures and tables

Extended Data Figure 1 Hair characterization in adult striped mice.

a, Striped mice have three different phenotypic categories of hair (light, black and banded) based on individual pigment pattern. All hair types have a black tip, which corresponds to structural hair features (not pigment). b, Relative proportion of light, black and banded guard and awl hair along the striped mouse dorsoventral axis (n = 5; error bars represent s.e.m.). a, Scale bar, 100 μm.

Source data

Extended Data Figure 2 Stripe-like differences in hair length along the dorsum in striped mouse embryos and pups.

ac, Flat-mount skin preparations (dermis up) of embryos at E16 (a) and E19 (b) and P2 pups (c). Middle axis is indicated in all cases (midline). White dashed lines mark regions differing in hair length at E19 (b) and regions differing in pigmentation at P2 (c). Incipient pigmentation stripes are shown in (b). d, Skin punches (1 mm) and length measurements show differences between hair in the dark and light stripe of P2 individuals. Hair length differences in (b) (incipient stripes) correlate with those seen when pigment differences arise (c, d). Differences among dorsal regions were evaluated by ANOVA followed by a Tukey–Kramer test; n = 15 per region; **P < 0.01; ***P < 0.001. Red lines depict the mean. e, Hair length measurements taken from guard, awl and zigzag hair found along the dorsum of adults. Differences among dorsal regions were evaluated by ANOVA followed by a Tukey–Kramer test; n = 24 (guard), 12 (awl) and 12 (zigzag) per region; P = 0.1736 (guard hair), P = 0.8006 (awl hair), P = 0.1038 (zigzag hair). Red lines depict the mean. f, Predicted probabilities of the observed stripe-like phenotypes, as inferred by supervised learning models built and trained to recognize time-point-specific gene expression signatures of the stripes. Bars reflect average probabilities ± s.e.m. computed from 30 consecutive iterations of the predictive model in each analysis. Labels indicate, as a ratio, the time point at which the randomForests model was applied to predict the stripe-like phenotype (the left term of the ratio), and the time point at which the model was built and trained (the right term of the ratio). The dotted line indicates the prior probability of either stripe phenotype (that is, 50% in case of only two distinct phenotypes). See Methods for details.

Source data

Extended Data Figure 3 Cell proliferation and hair follicle density in P2 striped mice.

a, Counts of proliferating cells, as determined by EdU labelling, in the epidermis and inside hair follicles (epidermal cells, dark stripe 1 versus light stripe, two-tailed t-test; n = 15 images per region; P = 0.5417; cells counted: 402 (dark stripe 1) and 444 (light stripe); intrafollicular cells, dark stripe 1 versus light stripe, two-tailed t-test; n = 12 images per region; P = 0.7537; cells counted: 724 (dark stripe 1) and 680 (light stripe)). Dotted lines delineate the epidermal compartment and the hair bulb. b, Number of hair follicles per surface area along the dorsoventral axis. Differences among dorsal regions were evaluated by ANOVA; n = 10 images per region; P = 0.4391; number of hair follicles counted: 139 (light stripe), 141 (dark stripe 1), 132 (dark stripe 2) and 128 (flank). Bright field images in a depict pigment. Boxes represent the 25th to 75th percentile, whiskers show the minimum and maximum value, and the horizontal line indicates the median. Red bars indicate the mean. Scale bars in a 100 μm, b 200 μm.

Source data

Extended Data Figure 4 RNA-seq analysis.

ad, Venn diagrams showing numbers of differentially expressed genes identified using either the M. musculus reference or the striped mouse de novo transcriptome assembly in light versus dark stripes (a), light versus flank (b), and flank versus dark (c), or differentially expressed genes in light or dark stripes versus the other skin region (light or dark stripes and the flank) (d). Genes that are specifically upregulated only in the dark or light stripes are highlighted in red. e, f, RNA-seq transcript levels (normalized gene counts) plotted as a function of differential expression (log2 fold-change). e, The 1,777 genes demonstrating significant (FDR < 0.1) differential expression in the light stripe versus the flank are shown in yellow (higher expression in the light stripe) or blue (higher expression in the flank). Four differentially expressed pigmentation-related genes are highlighted (dark yellow or dark blue), while 11 additional pigmentation-related genes that are not differentially expressed are shown in pink (Supplementary Table 1b). f, The 1,148 genes demonstrating significant (FDR < 0.1) differential expression in the flank versus the dark stripe are shown in yellow (higher expression in the flank) or blue (higher expression in the dark stripe). Eleven differentially expressed pigmentation-related genes are highlighted (dark yellow or dark blue), while six additional pigmentation-related genes that are not differentially expressed are shown in pink (Supplementary Table 1c).

Extended Data Figure 5 Stage-specific gene expression.

ac, Quantitative PCR of the relative mRNA levels of pigment-type switching genes Asip (a), Edn3 (b), and melanin synthesis genes Tyr and Tyrp1 (c) in different regions of the striped mouse skin and at different time points. Differences among stripes within each time point were evaluated by ANOVA followed by a Tukey–Kramer test; n = 4 per time point; *P < 0.05; **P < 0.01; ***P < 0.001. Red bars indicate the mean.

Source data

Extended Data Figure 6 Gain- and loss-of-function experiments in cultured cells.

a, Lentiviral constructs were modified from PLKO.1, a generic vector for expressing human RNU6-1 promoter-driven short hairpin RNAs (red loop). LTR, long terminal repeat; ψ, retroviral packaging element, RRE, Rev response element; cPPT, central polypurine tract; PGK, phosphoglycerate kinase promoter; H2B–GFP, Hist2h2be fused to GFP cDNA; P2A, 2A peptide. b, Western blot for expression of ALX3 in nuclear extracts of B16-F1 cells. Positive controls were extracts from mouse embryonic mesenchyme (MEM) or COS cells transfected with a pcDNA–ALX3 expression vector. COS cells transfected with an empty pcDNA vector served as negative controls. Actin immunoreactivity is shown below for the same extracts as a control. For gel source images, see Supplementary Fig. 1. c, d, Quantitative PCR of Alx3 (white), Mitf (black) and Silver (grey) mRNA levels in cells transduced with LV–Alx3:GFP (c), relative to cells transduced with the LV–GFP control (LV–Alx3:GFP versus LV–GFP, two-tailed t-test; n = 3) or shRNA lentiviral constructs (d), relative to cells transduced with a scrambled control (shRNA1, 2, 3 or 4 versus shRNA scrambled, two-tailed t-test; n = 3). **P < 0.01; ***P < 0.001. Red bars indicate the mean.

Source data

Extended Data Figure 7 Co-culture experiments.

ad, Wild-type B16 melanocytes (B16 wild-type (WT)) were exposed to keratinocytes (a) or melanocytes (c) stably transduced with either LV–Alx3:GFP (LV–Alx3 in graphs) or LV–GFP. b, d, Quantitative PCR of levels of Alx3 mRNA in cells carrying the lentiviral constructs (grey panel) and of Mitf, Tyr and Silver mRNA in B16 wild-type melanocytes exposed to keratinocytes (b) or melanocytes (d) transduced with LV–Alx3:GFP (blue panels) or LV–GFP (red panels) (LV–Alx3:GFP versus LV–GFP, two-tailed t-test; n = 3, ***P < 0.001; NS, not significant). Red bars in b and d indicate the mean.

Source data

Extended Data Figure 8 Ultrasound-guided in utero lentiviral injections.

af, Hair follicles from embryos injected at E8.5 with lentiviruses stained for SOX10 (a, d), virus transduced cells (b, e) and merged images with arrowheads showing SOX+ GFP+ cells (c, f). Dotted lines (af) delineate the hair bulb. g, Number of detectable SOX10+ cells (LV–Alx3:GFP versus LV–GFP, two-tailed t-test; n = 60; P = 0.1173; cells counted: 426 cells (LV–Alx3:GFP) and 398 cells (LV–GFP)). ho, Effect of Alx3 on skin. Hair follicles from samples injected with LV–GFP control and LV–Alx3:GFP depicting immunohistochemistry for K14 (h, k), virus transduced cells (i, l), and merged images showing K14+ GFP+ cells (j, m). n, Number of detectable K14+ GFP+ cells per follicular area (LV–Alx3:GFP versus LV–GFP, two-tailed t-test; n = 40, P = 0.275; average: 52.809 cells per hair follicle area (LV–Alx3:GFP) and 55.123 cells per hair follicle area (LV–GFP)). o, Hair follicle density in samples injected with viruses (LV–Alx3:GFP versus LV–GFP, two-tailed t-test; n = 30; P = 0.103; average: 0.84 hair follicles per surface area (LV–Alx3:GFP) and 0.794 hair follicles per surface area (LV–GFP)). Boxes represent the 25th to 75th percentile, whiskers show the minimum and maximum value, and the horizontal line indicates the median. Scale bars in af and hm are 50 μM.

Source data

Extended Data Figure 9 Alignment of a ~1.5-kb region of the Mitf M promoter in M. musculus and striped mouse.

Black boxes represent conserved sequences. Mapped onto the sequences are evolutionary conserved regions of the mammalian Mitf M promoter identified in silico (http://genome.ucsc.edu) (yellow), regions from which the EMSA probes were designed (red), and the transcription start site (green). The ten TAAT binding sites, conserved between M. musculus and striped mice (blue), which were tested are labelled sequentially.

Extended Data Figure 10 EMSA and luciferase assays.

a, EMSAs show the binding of nuclear proteins from B16-F1 cells to candidate-binding sites 3, 5 and 10. The absence (−) or presence of non-specific (NSC; 500-fold molar excess) or specific (SC; indicated fold molar excess) competing oligonucleotides, or the addition of ALX3 antibodies or control (NRS or IgG) is indicated. Arrows indicate complexes containing ALX3, arrowhead shows supershift for site 3 and asterisk highlights an artefact in the gel. b, EMSAs showing the binding of recombinant Alx3 synthesized using a rabbit reticulocyte lysate system to the indicated sites (sites 4–9). The absence (−) or presence of non-specific (NSC) or specific (SC) competing oligonucleotides (500-fold molar excess) is indicated. Note that site 5 is the only one showing sequence-specific binding. For gel source images, see Supplementary Fig. 1. c, Relative levels of luciferase activity in B16-F1 cells stably expressing GFP (dark circles) or Alx3 (light circles) for indicated binding sites. Luciferase activity was normalized relative to cells transfected with the empty reporter vector and values are given as a fraction of luminescence for GFP-transfected cells. Differences between cells transfected with LV–Alx3:GFP and LV–GFP for each plasmid were evaluated using two-tailed t-tests; n = 5; *P < 0.05; NS, not significant. Red lines depict the mean. Labels of mutated binding sites correspond to those described in Fig. 4a.

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Mallarino, R., Henegar, C., Mirasierra, M. et al. Developmental mechanisms of stripe patterns in rodents. Nature 539, 518–523 (2016). https://doi.org/10.1038/nature20109

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