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The genetic program for cartilage development has deep homology within Bilateria

Abstract

The evolution of novel cell types led to the emergence of new tissues and organs during the diversification of animals1. The origin of the chondrocyte, the cell type that synthesizes cartilage matrix, was central to the evolution of the vertebrate endoskeleton. Cartilage-like tissues also exist outside the vertebrates, although their relationship to vertebrate cartilage is enigmatic. Here we show that protostome and deuterostome cartilage share structural and chemical properties, and that the mechanisms of cartilage development are extensively conserved—from induction of chondroprogenitor cells by Hedgehog and β-catenin signalling, to chondrocyte differentiation and matrix synthesis by SoxE and SoxD regulation of clade A fibrillar collagen (ColA) genes—suggesting that the chondrogenic gene regulatory network evolved in the common ancestor of Bilateria. These results reveal deep homology of the genetic program for cartilage development in Bilateria and suggest that activation of this ancient core chondrogenic network underlies the parallel evolution of cartilage tissues in Ecdysozoa, Lophotrochozoa and Deuterostomia.

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Figure 1: Protostome invertebrate cartilage is structurally similar to vertebrate cartilage.
Figure 2: Deep conservation of gene expression during protostome cartilage development.
Figure 3: Cuttlefish chondrogenesis is regulated positively by Hh signalling and negatively by β-catenin.
Figure 4: Bilaterian cartilage development and the origin of the chondrocyte.

Accession codes

Primary accessions

NCBI Reference Sequence

Data deposits

Sequences generated in this work have been deposited in GenBank under accession numbers KP322116KP322126.

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Acknowledgements

We thank B. Battelle and members of H. J. Brockmann’s and David Julian’s laboratories for Limulus eggs, N. Brown for sharing protocols and reagents, N. Patel and the Limulus genome consortium for access to sequence data, and M. Welten and F. Leal for assisting with optical projection tomography and luciferase assays, respectively. This project was supported by the Howard Hughes Medical Institute (to M.J.C.). O.A.T. was a Howard Hughes Medical Institute International Student Research Fellow.

Author information

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Authors

Contributions

O.A.T. and M.J.C. designed the experiments, analysed the data and wrote the paper. O.A.T., L.A.S. and D.H.L. cloned Sepia and Limulus genes, analysed gene and protein expression, and performed histological analysis of adult tissues. O.A.T. isolated the full-length ColA cDNA, performed the optical projection tomography scanning and three-dimensional reconstructions, BrdU and small-molecule treatments, and the experiments on treated and control embryos. G.Z. isolated the full-length Sox9/SoxE genes and prepared the expression constructs for amphioxus, lamprey, hagfish and shark, and O.A.T. for zebrafish, cuttlefish and horseshoe crab. O.A.T. performed the cell culture and luciferase assays.

Corresponding author

Correspondence to Martin J. Cohn.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Developmental series showing chondrogenesis in Sepia and Limulus.

Masson’s trichrome-stained sections. Collagen is stained blue. ad, Sections through funnel cartilage of Sepia embryos. Bottom row shows high magnification of boxed area. Yellow arrowheads mark the pre-cartilaginous cell condensation and the yellow dashed line marks the level of the basal lamina of the funnel epithelium. ej, Transverse sections through the endosternite of Limulus embryos. Bottom row shows high magnification of boxed area. Yellow arrowheads mark the pre-cartilaginous cell condensations and the yellow dashed line delineates the mesenchyme from the yolk cavity.

Extended Data Figure 2 Molecular phylogenetic analysis of clade A fibrillar collagens and Sox transcription factors (SoxC, SoxD, SoxE and SoxF).

a, Molecular phylogeny clade A fibrillar collagens (ColA) using the carboxy (C)-terminal propeptide shows that that ColA genes are represented in all major lineages of Bilateria (Deuterostomia, purple; Annelida, green; Mollusca, cyan; Arthropoda, red) and indicates that Sepia and Limulus (orange arrowheads) sequences belong to the ColA family (see Supplementary Table 1 for sequence accession numbers). b, Shared architecture of ColA propeptide between vertebrates and protostome invertebrates. In vertebrates, the von Willebrand type C domain is absent in Col2α1 but present in the other clade A collagens (Col1α1, Col1α2, Col1α3 and Col2α5). c, Molecular phylogeny of Sox genes using the HMG DNA binding domain under the WAG amino-acid model of evolution. The sequences derived from Sepia and Limulus (in orange) belong to the SoxE and SoxD families (see Supplementary Table 2 for sequence access numbers). All trees were generated by Bayesian phylogenetic inference using WAG model of amino-acid substitution. Branch support shown as percentage of posterior probabilities.

Extended Data Figure 3 ColAa and ColAb show similar patterns of gene expression in Sepia embryos.

a, b, Whole-mount ISH for (a) ColAa and (b) ColAb. Dorsal views. c, Ventral view of ColAb ISH showing the funnel cartilage precursors, marked by green arrowheads. d, Cryosections of these embryos reveal that ColAb is expressed in pre-chondrogenic mesenchyme (green arrowhead). Funnel epithelium is marked by black open arrowhead. e, f, Negative control ISH for (e) SoxD and (d) SoxE using sense RNA probes; broken lines outline pre-chondrogenic cells that form the funnel cartilage.

Extended Data Figure 4 Chondrogenesis of multiple cartilages occurs near Hedgehog-expressing tissues in Sepia.

a, Funnel cartilage in a hatchling of Sepia (black arrows) located underneath the funnel epithelium (red arrowhead). b, Double ISH of the funnel cartilage primordium at stage 26, showing the expression of ColAa (brown stain) in pre-cartilaginous cells (green arrowheads) and Hedgehog (Hh; purple stain) in the funnel epithelium (red arrowhead). c, Fin cartilage located at the base of the fin (black arrows) in a hatchling. d, Double ISH of the fin at stage 26 showing pre-cartilaginous mesenchyme expressing ColAa (brown stain, green arrowheads) next to a Hh domain (purple stain, red arrowhead). e, Whole-mount alcian-blue-stained Sepia hatchling. The white dashed outline marks the right nuchal cartilage and the yellow dashed line indicates the approximate plane of the section shown in f, which is stained with Masson’s trichrome. g, Whole-mount ISH showing Hh expression on the right and left nuchal cartilage primordia at stage 26 (red arrowheads). A large domain of Hh expression can also be observed in the midline (black open arrowhead) between the nuchal cartilage primordium. Yellow dashed line in g indicates approximate plane of section shown in h, a cryosection showing the expression of Hh in the epithelium of the nuchal cartilage primordium (red arrowheads) but not in the mesenchyme (green open arrowhead). i, Whole-mount ISH of ColAa at stage 26 showing its expression on the nuchal cartilage primordia (green open arrowheads). Yellow dashed line in i indicates approximate plane of section shown in j, which shows a cryosection showing the expression of ColAa in the mesenchyme (green open arrowheads) of the nuchal cartilage primordium, but not in the epithelium (red arrowhead). k, Histological section stained with Masson’s trichrome at the level of the paired statocyst cavities surrounded by cranial cartilages. l, ISH on cryosections from a stage 26 embryo reveal that the brain (marked by a red asterisk) and most of the inner epithelial lining of the statocyst cavities express Hh (red open arrowheads). m, The pre-cartilaginous cells underneath the Hh domain express ColAa (marked by green open arrowheads).

Extended Data Figure 5 Patterns of gene expression in developing funnel cartilage of Sepia at stage 25.

a, Hh is expressed in the funnel epithelium. b, ColAa is expressed in pre-cartilaginous cells. c, SoxE is expressed in the funnel epithelium as well as in the pre-cartilaginous cells, similar to d. d, e, SoxD (d) and β-catenin (e) expression in the funnel cartilage progenitors. In all figures, red open arrowheads mark the funnel epithelium and green open arrowheads mark pre-cartilaginous cells. f, Schematic representation of the luciferase reporter assay to test the transactivation potential of Sox9/SoxE transcription factors. Cells were co-transfected with a Sox9/SoxE expression vector under the control of a ubiquitous CMV promoter. The luciferase reporter was controlled by upstream Col2a1 regulatory elements, four tandem copies of the chondrocyte-specific human Co2a1 enhancer, and the human Col2a1 promoter. g, SoxE and Sox9 transactivation of the human Col2a1 enhancer in NIH3T3 mouse fibroblast cells, assayed by the activity of a luciferase reporter driven by the Col2a1 enhancer. Asterisks indicate significant differences over control levels (t-test; P ≤ 0.05); error bars, s.d. Each luciferase experiment was repeated four times, with four replicates per experiment. h, PCNA immunofluorescence in the mature funnel cartilage of stage 28 embryos indicates active proliferation in the chondrocytes over the entire cartilaginous element (bottom panel shows high magnification of boxed area above; white open arrowhead marks the epithelium). Proliferation becomes restricted to the sub-epithelial layer one stage later (compare with Fig. 3).

Extended Data Figure 6 Gill and endosternite cartilages in Limulus are collagen-based and express SoxE during chondrogenesis.

a, Section through gills of Limulus hatchlings stained with Masson’s trichrome. Gill cartilage is located at the base of the gills (outlined by yellow dashed lines). b, Adult gill cartilage stained with Masson’s trichrome showing a cell-rich tissue with hypertrophic cells (black arrowhead) separated by thin extracellular matrix (black open arrowheads); the gill cartilage ECM shows no aniline blue stain compared with the surrounding connective tissue; however, during embryonic development SoxE (c) and ColA (d) are expressed in the gill cartilage primordia (green open arrowheads). ei, Confocal imaging of endosternite after phalloidin staining and ColA ISH. f, Higher magnification of the boxed area in e showing the boundary between ColA-expressing pre-chondrogenic cells (white arrowheads) and the differentiating muscle cells (white arrows) attached to the endosternite pre-chondrogenic tissue. gi, Separate channels from f, showing Hoescht (g), phalloidin (h) and ColA (i).

Extended Data Figure 7 Expression of β-catenin transcripts and protein after 5-day treatments with cyclopamine, SANT-1, alsterpaullone and DMSO (control).

ad, After treatment for 5 days with small-molecule inhibitors, β-catenin transcripts can be detected in the funnel cartilage primordium in the (a) DMSO controls as well as in (b) cyclopamine-, (c) SANT-1- and (d) alsterpaulone-treated embryos. ep, In contrast to β-catenin mRNA, β-catenin protein is degraded during normal funnel chondrogenesis, as seen in the DMSO control (e, m); however, β-catenin protein remains in funnel chondroprogenitors after treatment with cyclopamine (f, n), SANT-1 (g, o) and alsterpaullone (h, p).

Extended Data Figure 8 Bright-field micrographs and immunofluorescence of Sepia embryos before and after treatments with the small-molecule inhibitors cyclopamine, SANT-1 and alsterpaullone, or with DMSO vehicle control.

ac, Sepia embryos at the beginning of drug treatments (stages 23–24). d, Histological sections at the beginning of the treatments demonstrating the presence of the funnel epithelium and the associated mesenchyme. The cuboidal signalling epithelium (blue arrowhead) and pre-cartilaginous mesenchyme (green arrowhead) can be identified. et, Sepia embryos after 10 days of treatment: eg, control DMSO-treated embryos; ik, cyclopamine-treated embryos; mo, SANT-1-treated embryos; qs, alsterpaullone-treated embryos. h, l, p, t, PCNA staining shows that cell proliferation in funnel cartilage continued after drug treatments, indicating that treatments did not induce global toxicity. DMSO control (h) cyclopamine- (l) and SANT-1-treated (p) embryos stained positive for cell proliferation in the funnel cartilage, and alsterpaullone-treated (t) embryos showed stronger PCNA staining of the funnel cartilage than did cyclopamine-treated embryos, SANT-1-treated embryos or DMSO controls.

Extended Data Figure 9 Positive and negative modulation of β-catenin signalling has opposite effects on chondrogenesis in Sepia.

a, Stabilization of β-catenin signalling using the GSK-3β inhibitor BIO prevents funnel cartilage development, as revealed by Masson’s trichrome. b, c, Inhibition of β-catenin signalling by inducing axin stabilization (stabilization of β-catenin destruction complex) with IWR-1 (b) or by blocking the interaction of β-catenin and Tcf with PNU (c), did not disrupt chondrogenesis of funnel cartilage. dg, il, Cellular accumulation of β-catenin in funnel cartilage of alsterpaullone-treated embryos compared with DMSO controls. β-catenin nuclear localization is not observed in DMSO control embryos (d–g), but after alsterpaullone treatment, β-catenin accumulates in the cytoplasm and the nucleus (il). Arrowheads mark two cells stained with Hoechst (j) that are rich in β-catenin (k). g, l, Overlay of Hoechst/β-catenin from e and f (g) and j and k (l). h, m, Nuclear co-localization plots of funnel cartilage cells showing β-catenin intensities in Hoechst-positive domains (nuclei); cytoplasmic β-catenin signal is not plotted. Alsterpaullone-treated embryos (m) show higher β-catenin intensities than DMSO controls (h), demonstrating β-catenin accumulation in the nuclei. no, Accumulation of β-catenin does not affect Hh expression in the funnel epithelium after alsterpaullone treatments; compare o with DMSO controls in n.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion, Supplementary References and Supplementary Tables 1-4. (PDF 308 kb)

OPT 3D reconstruction

Alcian blue positive cartilaginous endoskeleton in a Sepia hatchling. (MPG 26170 kb)

OPT 3D reconstruction

Whole mount in situ hybridization showing ColAa expression in a Sepia embryo at stage 26. (MPG 20675 kb)

OPT 3D reconstruction

Whole mount in situ hybridization showing ColA expression in a Limulus embryo at stage 20. (MPG 16737 kb)

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Tarazona, O., Slota, L., Lopez, D. et al. The genetic program for cartilage development has deep homology within Bilateria. Nature 533, 86–89 (2016). https://doi.org/10.1038/nature17398

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