Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage
- Karolinska Institutet, Sweden
- Brno University of Technology, Czech Republic
- Uppsala University, Sweden
- Masaryk University, Czech Republic
- Medical University Vienna, Austria
- University of Michigan School of dentistry, United States
- Technische Universität Dresden, Germany
- University of Nebraska Medical Center, United States
- Royal Institute of Technology, Sweden
- John Innes Centre, United Kingdom
- National Institutes of Health, United States
Abstract
Cartilaginous structures are at the core of embryo growth and shaping before the bone forms. Here we report a novel principle of vertebrate cartilage growth that is based on introducing transversally-oriented clones into pre-existing cartilage. This mechanism of growth uncouples the lateral expansion of curved cartilaginous sheets from the control of cartilage thickness, a process which might be the evolutionary mechanism underlying adaptations of facial shape. In rod-shaped cartilage structures (Meckel, ribs and skeletal elements in developing limbs), the transverse integration of clonal columns determines the well-defined diameter and resulting rod-like morphology. We were able to alter cartilage shape by experimentally manipulating clonal geometries. Using in silico modeling, we discovered that anisotropic proliferation might explain cartilage bending and groove formation at the macro-scale.
Article and author information
Author details
Funding
European Molecular Biology Organization (ALTF 216-2013)
- Marketa Kaucka
Svenska Sällskapet för Medicinsk Forskning
- Marketa Kaucka
Svenska Forskningsrådet Formas
- Andreas Hellander
- Phillip T Newton
- Andrei S Chagin
- Kaj Fried
- Igor Adameyko
Karolinska Institutet
- Phillip T Newton
- Andrei S Chagin
- Kaj Fried
- Igor Adameyko
Bertil Hållstens Forskningsstiftelse
- Igor Adameyko
Åke Wiberg Stiftelse
- Igor Adameyko
National Institutes of Health
- Andreas Hellander
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Marianne Bronner, California Institute of Technology, United States
Ethics
Animal experimentation: All animal (mouse) work has been approved and permitted by the Ethical Committee on Animal Experiments (Norra Djurförsöksetiska Nämd, ethical permit N226/15 and N5/14) and conducted according to The Swedish Animal Agency´s Provisions and Guidelines for Animal Experimentation recommendations.
Version history
- Received: February 9, 2017
- Accepted: April 16, 2017
- Accepted Manuscript published: April 17, 2017 (version 1)
- Version of Record published: May 4, 2017 (version 2)
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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Oriented clonal cell dynamics enables accurate growth and shaping of vertebrate cartilage
eLife 6:e25902.
https://doi.org/10.7554/eLife.25902
Further reading
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- Developmental Biology
We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibroblast growth factor (FGF) signaling in germ layer specification and head-to-tail development of Xenopus embryos. Here, we present an extracellular proteolytic mechanism involving this serpin-protease system in the developing neural crest (NC). Knockdown of SerpinE2 by injected antisense morpholino oligonucleotides did not affect the specification of NC progenitors but instead inhibited the migration of NC cells, causing defects in dorsal fin, melanocyte, and craniofacial cartilage formation. Similarly, overexpression of the HtrA1 protease impaired NC cell migration and the formation of NC-derived structures. The phenotype of SerpinE2 knockdown was overcome by concomitant downregulation of HtrA1, indicating that SerpinE2 stimulates NC migration by inhibiting endogenous HtrA1 activity. SerpinE2 binds to HtrA1, and the HtrA1 protease triggers degradation of the cell surface proteoglycan Syndecan-4 (Sdc4). Microinjection of Sdc4 mRNA partially rescued NC migration defects induced by both HtrA1 upregulation and SerpinE2 downregulation. These epistatic experiments suggest a proteolytic pathway by a double inhibition mechanism:
SerpinE2 ┤HtrA1 protease ┤Syndecan-4 → NC cell migration.
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- Developmental Biology
- Neuroscience
Human fetal development has been associated with brain health at later stages. It is unknown whether growth in utero, as indexed by birth weight (BW), relates consistently to lifespan brain characteristics and changes, and to what extent these influences are of a genetic or environmental nature. Here we show remarkably stable and lifelong positive associations between BW and cortical surface area and volume across and within developmental, aging and lifespan longitudinal samples (N = 5794, 4–82 y of age, w/386 monozygotic twins, followed for up to 8.3 y w/12,088 brain MRIs). In contrast, no consistent effect of BW on brain changes was observed. Partly environmental effects were indicated by analysis of twin BW discordance. In conclusion, the influence of prenatal growth on cortical topography is stable and reliable through the lifespan. This early-life factor appears to influence the brain by association of brain reserve, rather than brain maintenance. Thus, fetal influences appear omnipresent in the spacetime of the human brain throughout the human lifespan. Optimizing fetal growth may increase brain reserve for life, also in aging.
