The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition

  1. Chengdong Liu
  2. Shuang Li
  3. Pernille Rimmer Noer
  4. Kasper Kjaer-Sorensen
  5. Anna Karina Juhl
  6. Allison Goldstein
  7. Caihuan Ke
  8. Claus Oxvig  Is a corresponding author
  9. Cunming Duan  Is a corresponding author
  1. University of Michigan, United States
  2. Aarhus University, Denmark
  3. Xiamen University, China

Abstract

Human patients carrying PAPP‐A2 inactivating mutations have low bone mineral density. The underlying mechanisms for this reduced calcification are poorly understood. Using a zebrafish model, we report that Papp-aa regulates bone calcification by promoting Ca2+-transporting epithelial cell (ionocyte) quiescence-proliferation transition. Ionocytes, which are normally quiescent, re-enter the cell cycle under low [Ca2+] stress. Genetic deletion of Papp-aa, but not the closely related Papp-ab, abolished ionocyte proliferation and reduced calcified bone mass. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-Akt-Tor signaling in ionocytes. Under low Ca2+ stress, Papp-aa cleaved Igfbp5a. Under normal conditions, however, Papp-aa proteinase activity was suppressed and IGFs were sequestered in the IGF/Igfbp complex. Pharmacological disruption of the IGF/Igfbp complex or adding free IGF1 activated IGF signaling and promoted ionocyte proliferation. These findings suggest that Papp-aa-mediated local Igfbp5a cleavage functions as a [Ca2+]-regulated molecular switch linking IGF signaling to bone calcification by stimulating epithelial cell quiescence-proliferation transition under low Ca2+ stress.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Chengdong Liu

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Shuang Li

    Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pernille Rimmer Noer

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  4. Kasper Kjaer-Sorensen

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  5. Anna Karina Juhl

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Allison Goldstein

    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Caihuan Ke

    College of Ocean and Earth Sciences, Xiamen University, Xiamen, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Claus Oxvig

    Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
    For correspondence
    co@mb.au.dk
    Competing interests
    The authors declare that no competing interests exist.
  9. Cunming Duan

    Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States
    For correspondence
    cduan@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6794-2762

Funding

National Science Foundation (IOS-1557850)

  • Cunming Duan

Lundbeck (Grant R317-2019-526)

  • Claus Oxvig

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

Reviewing Editor

  1. Cheryl Ackert-Bicknell, University of Colorado, United States

Ethics

Animal experimentation: All experiments were conducted in accordance with the guidelines approved by the Institutional Committee on the Use and Care of Animals, University of Michigan and the Danish The Animal Experiments Inspectorate (permit numbers 2017-15-0201-01369 and 2017-15-0202-00098).

Version history

  1. Received: September 30, 2019
  2. Accepted: April 11, 2020
  3. Accepted Manuscript published: April 15, 2020 (version 1)
  4. Accepted Manuscript updated: April 16, 2020 (version 2)
  5. Version of Record published: April 27, 2020 (version 3)
  6. Version of Record updated: May 15, 2020 (version 4)

Copyright

© 2020, Liu 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

  • 1,263
    Page views
  • 200
    Downloads
  • 9
    Citations

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. Chengdong Liu
  2. Shuang Li
  3. Pernille Rimmer Noer
  4. Kasper Kjaer-Sorensen
  5. Anna Karina Juhl
  6. Allison Goldstein
  7. Caihuan Ke
  8. Claus Oxvig
  9. Cunming Duan
(2020)
The metalloproteinase Papp-aa controls epithelial cell quiescence-proliferation transition
eLife 9:e52322.
https://doi.org/10.7554/eLife.52322

Share this article

https://doi.org/10.7554/eLife.52322

Further reading

    1. Developmental Biology
    2. Immunology and Inflammation
    Amir Hossein Kayvanjoo, Iva Splichalova ... Elvira Mass
    Research Article Updated

    During embryogenesis, the fetal liver becomes the main hematopoietic organ, where stem and progenitor cells as well as immature and mature immune cells form an intricate cellular network. Hematopoietic stem cells (HSCs) reside in a specialized niche, which is essential for their proliferation and differentiation. However, the cellular and molecular determinants contributing to this fetal HSC niche remain largely unknown. Macrophages are the first differentiated hematopoietic cells found in the developing liver, where they are important for fetal erythropoiesis by promoting erythrocyte maturation and phagocytosing expelled nuclei. Yet, whether macrophages play a role in fetal hematopoiesis beyond serving as a niche for maturing erythroblasts remains elusive. Here, we investigate the heterogeneity of macrophage populations in the murine fetal liver to define their specific roles during hematopoiesis. Using a single-cell omics approach combined with spatial proteomics and genetic fate-mapping models, we found that fetal liver macrophages cluster into distinct yolk sac-derived subpopulations and that long-term HSCs are interacting preferentially with one of the macrophage subpopulations. Fetal livers lacking macrophages show a delay in erythropoiesis and have an increased number of granulocytes, which can be attributed to transcriptional reprogramming and altered differentiation potential of long-term HSCs. Together, our data provide a detailed map of fetal liver macrophage subpopulations and implicate macrophages as part of the fetal HSC niche.

    1. Developmental Biology
    2. Neuroscience
    Smrithi Prem, Bharati Dev ... Emanuel DiCicco-Bloom
    Research Article Updated

    Autism spectrum disorder (ASD) is defined by common behavioral characteristics, raising the possibility of shared pathogenic mechanisms. Yet, vast clinical and etiological heterogeneity suggests personalized phenotypes. Surprisingly, our iPSC studies find that six individuals from two distinct ASD subtypes, idiopathic and 16p11.2 deletion, have common reductions in neural precursor cell (NPC) neurite outgrowth and migration even though whole genome sequencing demonstrates no genetic overlap between the datasets. To identify signaling differences that may contribute to these developmental defects, an unbiased phospho-(p)-proteome screen was performed. Surprisingly despite the genetic heterogeneity, hundreds of shared p-peptides were identified between autism subtypes including the mTOR pathway. mTOR signaling alterations were confirmed in all NPCs across both ASD subtypes, and mTOR modulation rescued ASD phenotypes and reproduced autism NPC-associated phenotypes in control NPCs. Thus, our studies demonstrate that genetically distinct ASD subtypes have common defects in neurite outgrowth and migration which are driven by the shared pathogenic mechanism of mTOR signaling dysregulation.