Amotl2a interacts with the Hippo effector Yap1 and the Wnt/β-catenin effector Lef1 to control tissue size in zebrafish

Abstract

During development, proliferation must be tightly controlled for organs to reach their appropriate size. While the Hippo signaling pathway plays a major role in organ growth control, how it senses and responds to increased cell density is still unclear. Here we use the zebrafish lateral line primordium (LLP), a group of migrating epithelial cells that form sensory organs, to understand how tissue growth is controlled during organ formation. Loss of the cell junction-associated Motin protein Amotl2a leads to overproliferation and bigger LLP, affecting the final pattern of sensory organs. Amotl2a function in the LLP is mediated together by the Hippo pathway effector Yap1 and the Wnt/β-catenin effector Lef1. Our results implicate for the first time the Hippo pathway in size regulation in the LL system. We further provide evidence that the Hippo/Motin interaction is essential to limit tissue size during development.

Article and author information

Author details

  1. Sobhika Agarwala

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Sandra Duquesne

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Kun Liu

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Anton Boehm

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Lin Grimm

    Developmental Biology, Institute for Biology I, Faculty of Biology, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Sandra Link

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Sabine König

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Stefan Eimer

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Olaf Ronneberger

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Virginie Lecaudey

    BIOSS Centre for Biological Signalling Studies, Albert Ludwigs University of Freiburg, Freiburg im Breisgau, Germany
    For correspondence
    Lecaudey@bio.uni-frankfurt.de
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Tanya T Whitfield, University of Sheffield, United Kingdom

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations of the German Animal Welfare Act (TierSchG) based on the directive 2010/63/UE of the European parlament. All of the animals were handled according to approved institutional animal care at the University of Freiburg and approved by the local government (Regierungspräsidium Freiburg -Permit Number: G-09/05).

Version history

  1. Received: April 18, 2015
  2. Accepted: September 2, 2015
  3. Accepted Manuscript published: September 3, 2015 (version 1)
  4. Version of Record published: October 16, 2015 (version 2)

Copyright

© 2015, Agarwala 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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  1. Sobhika Agarwala
  2. Sandra Duquesne
  3. Kun Liu
  4. Anton Boehm
  5. Lin Grimm
  6. Sandra Link
  7. Sabine König
  8. Stefan Eimer
  9. Olaf Ronneberger
  10. Virginie Lecaudey
(2015)
Amotl2a interacts with the Hippo effector Yap1 and the Wnt/β-catenin effector Lef1 to control tissue size in zebrafish
eLife 4:e08201.
https://doi.org/10.7554/eLife.08201

Share this article

https://doi.org/10.7554/eLife.08201

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    The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.