Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

Dylan J. M. Bergen; Qiao Tong; Ankit Shukla; Elis Newham; Jan Zethof; Mischa Lundberg; Rebecca Ryan; Scott E. Youlten; Monika Frysz; Peter I. Croucher; Gert Flik; Rebecca J. Richardson; John P. Kemp; Chrissy L. Hammond; Juriaan R. Metz

doi:10.1186/s12915-021-01209-8

Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

Dylan J. M. Bergen^*, Qiao Tong, Ankit Shukla, Elis Newham, Jan Zethof, Mischa Lundberg, Rebecca Ryan, Scott E. Youlten, Monika Frysz, Peter I. Croucher, Gert Flik, Rebecca J. Richardson, John P. Kemp, Chrissy L. Hammond, Juriaan R. Metz^*

^*Corresponding author for this work

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31 Citations (Scopus)

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Abstract

Background
Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration.

Results
We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10−3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10−4), and estimated bone mineral density (eBMD, P< 2× 10−5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10−24) or eBMD (SPP1, P=6× 10−20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects.

Conclusion
We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.

Original language	English
Article number	21
Number of pages	25
Journal	BMC Biology
Volume	20
Issue number	1
DOIs	https://doi.org/10.1186/s12915-021-01209-8
Publication status	Published - 21 Jan 2022

Bibliographical note

Funding Information:
DB and CH received Fellowship funding from Versus Arthritis (22044 and 21937 respectively). JM and GF were supported by the subsidy programme Smartmix (SSM06010) of the Dutch Ministries of Economic Affairs and Education, Culture and Science. JPK was funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938) and project grant (GNT1158758). ML is supported by a UQ Research Training Scholarship and the Commonwealth Scientific and Industrial Research Organisation Postgraduate Top-Up Scholarship. RR and RJR were supported by the BHF Oxbridge Centre of Regenerative Medicine (RM/17/2/33380) and a BHF Intermediate Fellowship to RJR (FS/15/2/31225).

Publisher Copyright:
© 2021, The Author(s).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

osteoanabolic
osteoblast
zebrafish
regeneration
transcriptome
genetics
transgenic
collagen
bone
musculoskeletal disorders

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10.1186/s12915-021-01209-8

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High Bone Mass Disorders: New Insights from Connecting the Clinic and the Bench
Bergen, D. J. M., Maurizi, A., Formosa, M. M., Mcdonald, G., El-Gazzar, A., Hassan, N., Brandi, M.-L., Riancho, J. A., Rivadeneira, F., Ntzani, E., Duncan, E. L., Gregson, C. L., Kiel, D. P., Zillikens, M. C., Sangiorgi, L., Högler, W., Duran, I., Mäkitie, O., van Hul, W. & Hendrickx, G., 26 Sept 2022, (E-pub ahead of print) In: Journal of Bone and Mineral Research.
Research output: Contribution to journal › Review article (Academic Journal) › peer-review

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14 Citations (Scopus)

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Zebrafish as an emerging model for osteoporosis: a primary testing platform for screening new osteo-active compounds
Bergen, D., Kague, E. & Hammond, C., 29 Jan 2019, In: Frontiers in Endocrinology. 10, JAN, 20 p., 6.
Research output: Contribution to journal › Review article (Academic Journal) › peer-review

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Functional validation of novel osteo-anabolic factors in the zebrafish
Bergen, D. J. M. (Principal Investigator)
1/04/19 → …
Project: Research

Determining new osteo-anabolic targets using zebrafish models of human genomic study discoveries.
Bergen, D. J. M. (Recipient)
1 Apr 2019 → 31 Mar 2022
Activity: Other activity types › Fellowship awarded competitively

Cite this

Bergen, D. J. M., Tong, Q., Shukla, A., Newham, E., Zethof, J., Lundberg, M., Ryan, R., Youlten, S. E., Frysz, M., Croucher, P. I., Flik, G., Richardson, R. J., Kemp, J. P., Hammond, C. L., & Metz, J. R. (2022). Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease. BMC Biology, 20(1), Article 21. https://doi.org/10.1186/s12915-021-01209-8

@article{d9cafb27803348e5b25889c843dfa3e9,

title = "Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease",

abstract = "Background Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. Results We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10−3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10−4), and estimated bone mineral density (eBMD, P< 2× 10−5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10−24) or eBMD (SPP1, P=6× 10−20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects. Conclusion We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.",

keywords = "osteoanabolic, osteoblast, zebrafish, regeneration, transcriptome, genetics, transgenic, collagen, bone, musculoskeletal disorders",

author = "Bergen, \{Dylan J. M.\} and Qiao Tong and Ankit Shukla and Elis Newham and Jan Zethof and Mischa Lundberg and Rebecca Ryan and Youlten, \{Scott E.\} and Monika Frysz and Croucher, \{Peter I.\} and Gert Flik and Richardson, \{Rebecca J.\} and Kemp, \{John P.\} and Hammond, \{Chrissy L.\} and Metz, \{Juriaan R.\}",

note = "Funding Information: DB and CH received Fellowship funding from Versus Arthritis (22044 and 21937 respectively). JM and GF were supported by the subsidy programme Smartmix (SSM06010) of the Dutch Ministries of Economic Affairs and Education, Culture and Science. JPK was funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938) and project grant (GNT1158758). ML is supported by a UQ Research Training Scholarship and the Commonwealth Scientific and Industrial Research Organisation Postgraduate Top-Up Scholarship. RR and RJR were supported by the BHF Oxbridge Centre of Regenerative Medicine (RM/17/2/33380) and a BHF Intermediate Fellowship to RJR (FS/15/2/31225). Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2022",

month = jan,

day = "21",

doi = "10.1186/s12915-021-01209-8",

language = "English",

volume = "20",

journal = "BMC Biology",

issn = "1741-7007",

publisher = "BioMed Central Ltd",

number = "1",

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Bergen, DJM, Tong, Q, Shukla, A, Newham, E, Zethof, J, Lundberg, M, Ryan, R, Youlten, SE, Frysz, M, Croucher, PI, Flik, G, Richardson, RJ, Kemp, JP, Hammond, CL & Metz, JR 2022, 'Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease', BMC Biology, vol. 20, no. 1, 21. https://doi.org/10.1186/s12915-021-01209-8

TY - JOUR

T1 - Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

AU - Bergen, Dylan J. M.

AU - Tong, Qiao

AU - Shukla, Ankit

AU - Newham, Elis

AU - Zethof, Jan

AU - Lundberg, Mischa

AU - Ryan, Rebecca

AU - Youlten, Scott E.

AU - Frysz, Monika

AU - Croucher, Peter I.

AU - Flik, Gert

AU - Richardson, Rebecca J.

AU - Kemp, John P.

AU - Hammond, Chrissy L.

AU - Metz, Juriaan R.

N1 - Funding Information: DB and CH received Fellowship funding from Versus Arthritis (22044 and 21937 respectively). JM and GF were supported by the subsidy programme Smartmix (SSM06010) of the Dutch Ministries of Economic Affairs and Education, Culture and Science. JPK was funded by a National Health and Medical Research Council (Australia) Investigator grant (GNT1177938) and project grant (GNT1158758). ML is supported by a UQ Research Training Scholarship and the Commonwealth Scientific and Industrial Research Organisation Postgraduate Top-Up Scholarship. RR and RJR were supported by the BHF Oxbridge Centre of Regenerative Medicine (RM/17/2/33380) and a BHF Intermediate Fellowship to RJR (FS/15/2/31225). Publisher Copyright: © 2021, The Author(s).

PY - 2022/1/21

Y1 - 2022/1/21

N2 - Background Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. Results We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10−3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10−4), and estimated bone mineral density (eBMD, P< 2× 10−5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10−24) or eBMD (SPP1, P=6× 10−20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects. Conclusion We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.

AB - Background Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration. Results We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10−3). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10−4), and estimated bone mineral density (eBMD, P< 2× 10−5). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10−24) or eBMD (SPP1, P=6× 10−20) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2Y228X/Y228X mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1P160X/P160X mutants predominantly showed mineralisation defects. Conclusion We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.

KW - osteoanabolic

KW - osteoblast

KW - zebrafish

KW - regeneration

KW - transcriptome

KW - genetics

KW - transgenic

KW - collagen

KW - bone

KW - musculoskeletal disorders

U2 - 10.1186/s12915-021-01209-8

DO - 10.1186/s12915-021-01209-8

M3 - Article (Academic Journal)

C2 - 35057801

SN - 1741-7007

VL - 20

JO - BMC Biology

JF - BMC Biology

IS - 1

M1 - 21

ER -

Regenerating zebrafish scales express a subset of evolutionary conserved genes involved in human skeletal disease

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

Handle.net

Fingerprint

Research output

High Bone Mass Disorders: New Insights from Connecting the Clinic and the Bench

Zebrafish as an emerging model for osteoporosis: a primary testing platform for screening new osteo-active compounds

Projects

Functional validation of novel osteo-anabolic factors in the zebrafish

Activities

Determining new osteo-anabolic targets using zebrafish models of human genomic study discoveries.

Cite this