Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors

  1. Michael S Fleming
  2. Anna Vysochan
  3. Sόnia Paixão
  4. Jingwen Niu
  5. Rüdiger Klein
  6. Joseph M Savitt
  7. Wenqin Luo  Is a corresponding author
  1. University of Pennsylvania, United States
  2. Max Planck Institute of Neurobiology, Germany
  3. Parkinson's Disease and Movement Disorder Center of Maryland, United States

Abstract

RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfrα2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfrα2 null mice display comparable early central projection deficits, but Gfrα2 null RA mechanoreceptors recover later. Loss of Gfrα1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfrα1;Gfrα2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRα1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling.

Article and author information

Author details

  1. Michael S Fleming

    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anna Vysochan

    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Sόnia Paixão

    Molecules - Signals - Development, Max Planck Institute of Neurobiology, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Jingwen Niu

    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rüdiger Klein

    Molecules - Signals - Development, Max Planck Institute of Neurobiology, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Joseph M Savitt

    Parkinson's Disease and Movement Disorder Center of Maryland, Elkridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Wenqin Luo

    Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
    For correspondence
    luow@mail.med.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Mice except GDNFlacZ line were raised in a barrier facility in Hill Pavilion, the618 University of Pennsylvania. All procedures were conducted according to animal protocols619 approved by Institutional Animal Care and Use Committee (IACUC) of the University of620 Pennsylvania and National Institutes of Health guidelines. GDNFlacZ mice were raised in621 accordance with the European Community Council Directive of November 24, 1986622 (86/609/EEC), and approved by the ethics.

Copyright

© 2015, Fleming 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.

Metrics

  • 2,472
    views
  • 476
    downloads
  • 29
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Michael S Fleming
  2. Anna Vysochan
  3. Sόnia Paixão
  4. Jingwen Niu
  5. Rüdiger Klein
  6. Joseph M Savitt
  7. Wenqin Luo
(2015)
Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors
eLife 4:e06828.
https://doi.org/10.7554/eLife.06828

Share this article

https://doi.org/10.7554/eLife.06828

Further reading

    1. Developmental Biology
    2. Evolutionary Biology
    Hope M Healey, Hayden B Penn ... William A Cresko
    Research Article

    Seahorses, pipefishes, and seadragons are fishes from the family Syngnathidae that have evolved extraordinary traits including male pregnancy, elongated snouts, loss of teeth, and dermal bony armor. The developmental genetic and cellular changes that led to the evolution of these traits are largely unknown. Recent syngnathid genome assemblies revealed suggestive gene content differences and provided the opportunity for detailed genetic analyses. We created a single-cell RNA sequencing atlas of Gulf pipefish embryos to understand the developmental basis of four traits: derived head shape, toothlessness, dermal armor, and male pregnancy. We completed marker gene analyses, built genetic networks, and examined the spatial expression of select genes. We identified osteochondrogenic mesenchymal cells in the elongating face that express regulatory genes bmp4, sfrp1a, and prdm16. We found no evidence for tooth primordia cells, and we observed re-deployment of osteoblast genetic networks in developing dermal armor. Finally, we found that epidermal cells expressed nutrient processing and environmental sensing genes, potentially relevant for the brooding environment. The examined pipefish evolutionary innovations are composed of recognizable cell types, suggesting that derived features originate from changes within existing gene networks. Future work addressing syngnathid gene networks across multiple stages and species is essential for understanding how the novelties of these fish evolved.

    1. Developmental Biology
    2. Neuroscience
    Taro Ichimura, Taishi Kakizuka ... Takeharu Nagai
    Tools and Resources

    We established a volumetric trans-scale imaging system with an ultra-large field-of-view (FOV) that enables simultaneous observation of millions of cellular dynamics in centimeter-wide three-dimensional (3D) tissues and embryos. Using a custom-made giant lens system with a magnification of ×2 and a numerical aperture (NA) of 0.25, and a CMOS camera with more than 100 megapixels, we built a trans-scale scope AMATERAS-2, and realized fluorescence imaging with a transverse spatial resolution of approximately 1.1 µm across an FOV of approximately 1.5×1.0 cm2. The 3D resolving capability was realized through a combination of optical and computational sectioning techniques tailored for our low-power imaging system. We applied the imaging technique to 1.2 cm-wide section of mouse brain, and successfully observed various regions of the brain with sub-cellular resolution in a single FOV. We also performed time-lapse imaging of a 1-cm-wide vascular network during quail embryo development for over 24 hr, visualizing the movement of over 4.0×105 vascular endothelial cells and quantitatively analyzing their dynamics. Our results demonstrate the potential of this technique in accelerating production of comprehensive reference maps of all cells in organisms and tissues, which contributes to understanding developmental processes, brain functions, and pathogenesis of disease, as well as high-throughput quality check of tissues used for transplantation medicine.