A new mode of pancreatic islet innervation revealed by live imaging in zebrafish

  1. Yu Hsuan Carol Yang  Is a corresponding author
  2. Koichi Kawakami
  3. Didier YR Stainier  Is a corresponding author
  1. Max Planck Institute for Heart and Lung Research, Germany
  2. National Institute of Genetics, Japan


Pancreatic islets are innervated by autonomic and sensory nerves that influence their function. Analyzing the innervation process should provide insight into the nerve-endocrine interactions and their roles in development and disease. Here, using in vivo time-lapse imaging and genetic analyses in zebrafish, we determined the events leading to islet innervation. Comparable neural density in the absence of vasculature indicates that it is dispensable for early pancreatic innervation. Neural crest cells are in close contact with endocrine cells early in development. We find these cells give rise to neurons that extend axons towards the islet as they surprisingly migrate away. Specific ablation of these neurons partly prevents other neurons from migrating away from the islet resulting in diminished innervation. Thus, our studies establish the zebrafish as a model to interrogate mechanisms of organ innervation, and reveal a novel mode of innervation whereby neurons establish connections with their targets before migrating away.

Data availability

All data generated/analysed during this study are included in the manuscript. Individual replicates along with the means+/- SEM are plotted for all numerical data in the figures.

Article and author information

Author details

  1. Yu Hsuan Carol Yang

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    Competing interests
    No competing interests declared.
  2. Koichi Kawakami

    Division of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9993-1435
  3. Didier YR Stainier

    Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    Competing interests
    Didier YR Stainier, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0382-0026


Max Planck Society (Open-access funding)

  • Didier YR Stainier

Human Frontier Science Program (Long-Term Fellowship)

  • Yu Hsuan Carol Yang

European Molecular Biology Organization (Long-Term Fellowship)

  • Yu Hsuan Carol Yang

Canadian Institutes of Health Research (CIHR Fellowship)

  • Yu Hsuan Carol Yang

Japan Agency for Medical Research and Development (NBRP)

  • Koichi Kawakami

National Institute of Genetics (NIG-JOINT Collaborative Research (A2))

  • Yu Hsuan Carol Yang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.


Animal experimentation: All zebrafish husbandry was performed under standard conditions in accordance with institutional (MPG) and national ethical and animal welfare guidelines approved by the ethics committee for animal experiments at the Regierungspräsidium Darmstadt, Germany (permit numbers B2/1138 and B2/Anz. 1007).

Reviewing Editor

  1. Judith Eisen, University of Oregon, United States

Publication history

  1. Received: December 21, 2017
  2. Accepted: June 18, 2018
  3. Accepted Manuscript published: June 19, 2018 (version 1)
  4. Version of Record published: July 10, 2018 (version 2)


© 2018, Yang 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.


  • 4,565
    Page views
  • 514
  • 15

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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. Yu Hsuan Carol Yang
  2. Koichi Kawakami
  3. Didier YR Stainier
A new mode of pancreatic islet innervation revealed by live imaging in zebrafish
eLife 7:e34519.

Further reading

    1. Cell Biology
    Enric Gutiérrez-Martínez, Susana Benet Garrab ... Maria F Garcia-Parajo
    Research Article

    The immunoglobulin-like lectin receptor CD169 (Siglec-1) mediates the capture of HIV-1 by activated dendritic cells (DC) through binding to sialylated ligands. These interactions result in a more efficient virus capture as compared to resting DCs, although the underlying mechanisms are poorly understood. Using a combination of super-resolution microscopy, single particle tracking and biochemical perturbations we studied the nanoscale organization of Siglec-1 on activated DCs and its impact on viral capture and its trafficking to a single viral-containing compartment. We found that activation of DCs leads to Siglec-1 basal nanoclustering at specific plasma membrane regions where receptor diffusion is constrained by Rho-ROCK activation and formin-dependent actin polymerization. Using liposomes with varying ganglioside concentrations, we further demonstrate that Siglec-1 nanoclustering enhances the receptor avidity to limiting concentrations of gangliosides carrying sialic ligands. Binding to either HIV-1 particles or ganglioside-bearing liposomes lead to enhanced Siglec-1 nanoclustering and global actin rearrangements characterized by a drop in RhoA activity, facilitating the final accumulation of viral particles in a single sac-like compartment. Overall, our work provides new insights on the role of the actin machinery of activated DCs in regulating the formation of basal Siglec-1 nanoclustering, being decisive for the capture and actin-dependent trafficking of HIV-1 into the virus-containing compartment.

    1. Cell Biology
    2. Neuroscience
    Yu Wang, Meghan Lee Arnold ... Barth D Grant
    Research Article Updated

    Caenorhabditis elegans neurons under stress can produce giant vesicles, several microns in diameter, called exophers. Current models suggest that exophers are neuroprotective, providing a mechanism for stressed neurons to eject toxic protein aggregates and organelles. However, little is known of the fate of the exopher once it leaves the neuron. We found that exophers produced by mechanosensory neurons in C. elegans are engulfed by surrounding hypodermal skin cells and are then broken up into numerous smaller vesicles that acquire hypodermal phagosome maturation markers, with vesicular contents gradually degraded by hypodermal lysosomes. Consistent with the hypodermis acting as an exopher phagocyte, we found that exopher removal requires hypodermal actin and Arp2/3, and the hypodermal plasma membrane adjacent to newly formed exophers accumulates dynamic F-actin during budding. Efficient fission of engulfed exopher-phagosomes to produce smaller vesicles and degrade their contents requires phagosome maturation factors SAND-1/Mon1, GTPase RAB-35, the CNT-1 ARF-GAP, and microtubule motor-associated GTPase ARL-8, suggesting a close coupling of phagosome fission and phagosome maturation. Lysosome activity was required to degrade exopher contents in the hypodermis but not for exopher-phagosome resolution into smaller vesicles. Importantly, we found that GTPase ARF-6 and effector SEC-10/exocyst activity in the hypodermis, along with the CED-1 phagocytic receptor, is required for efficient production of exophers by the neuron. Our results indicate that the neuron requires specific interaction with the phagocyte for an efficient exopher response, a mechanistic feature potentially conserved with mammalian exophergenesis, and similar to neuronal pruning by phagocytic glia that influences neurodegenerative disease.