BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity
- Stony Brook University, United States
- University of Edinburgh, United Kingdom
- Seattle Children's Research Institute, United States
Abstract
The mesodermal germ layer is patterned into mediolateral subtypes by signaling factors including BMP and FGF. How these pathways are integrated to induce specific mediolateral cell fates is not well understood. We used mesoderm derived from post-gastrulation neuromesodermal progenitors (NMPs), which undergo a binary mediolateral patterning decision, as a simplified model to understand how FGF acts together with BMP to impart mediolateral fate. Using zebrafish and mouse NMPs, we identify an evolutionarily conserved mechanism of BMP and FGF mediated mediolateral mesodermal patterning that occurs through modulation of basic helix-loop-helix (bHLH) transcription factor activity. BMP imparts lateral fate through induction of Id helix loop helix (HLH) proteins, which antagonize bHLH transcription factors, induced by FGF signaling, that specify medial fate. We extend our analysis of zebrafish development to show that bHLH activity is responsible for the mediolateral patterning of the entire mesodermal germ layer.
Data availability
Transgenic fish lines generated for this study will be made available through the Zebrafish International Resource Center. The raw data for the qPCR experiments is available as Figure 2-source data 1, Figure 5-source data 1 and Figure 6-source data 1.
Article and author information
Author details
Benjamin Louis Martin
Funding
National Science Foundation (CAREER Award IOS1452928)
- Benjamin Louis Martin
American Heart Association (National Scientist Development Grant 13SDG14360032)
- Benjamin Louis Martin
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03 AR065760)
- Lisa Maves
Medical Research Council (Mr/K011200/1)
- Valerie Wilson
Wellcome (Senior Fellowship in Basic Biomedical Science 103789/Z/14/Z)
- Sally Lowell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Deborah Yelon, University of California, San Diego, United States
Ethics
Animal experimentation: This study was performed in accordance with and approval from the Stony Brook University Institutional Animal Use and Care Committee (IACUC) (protocol # 301537), Seattle Children's Research Institute IACUC (protocol # 14109), and the Animal Welfare and Ethical Review Panel of the MRC Centre for Regenerative Medicine and within the conditions of the Animals (Scientific Procedures) Act of 1986 (UK Home Office project license PPL60/4435).
Version history
- Received: August 3, 2017
- Accepted: May 26, 2018
- Accepted Manuscript published: June 7, 2018 (version 1)
- Version of Record published: June 21, 2018 (version 2)
Copyright
© 2018, Row et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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BMP and FGF signaling interact to pattern mesoderm by controlling basic helix-loop-helix transcription factor activity
eLife 7:e31018.
https://doi.org/10.7554/eLife.31018
Further reading
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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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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.
