The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth

  1. Shu Yang
  2. Xuefeng Wu
  3. Euphrosyne I Daoutidou
  4. Ya Zhang
  5. MaryJane Shimell
  6. Kun-Han Chuang
  7. Aidan J Peterson
  8. Michael B O'Connor
  9. Xiaoyan Zheng  Is a corresponding author
  1. George Washington University, United States
  2. University of Minnesota, United States

Abstract

Hedgehog (Hh) and bone morphogenetic proteins (BMPs) pattern the developing Drosophila wing by functioning as short- and long-range morphogens, respectively. Here, we show that a previously unknown Hh-dependent mechanism fine-tunes the activity of BMPs. Through genome-wide expression profiling of the Drosophila wing imaginal discs, we identify nord as a novel target gene of the Hh signaling pathway. Nord is related to the vertebrate Neuron Derived Neurotrophic Factor (NDNF) involved in Congenital Hypogonadotropic Hypogonadism and several types of cancer. Loss- and gain-of-function analyses implicate Nord in the regulation of wing growth and proper crossvein patterning. At the molecular level, we present biochemical evidence that Nord is a secreted BMP-binding protein and localizes to the extracellular matrix. Nord binds to Decapentaplegic (Dpp) or the heterodimer Dpp-Glass bottom boat (Gbb) to modulate their release and activity. Furthermore, we demonstrate that Nord is a dosage-depend BMP modulator, where low levels of Nord promote and high levels inhibit BMP signaling. Taken together, we propose that Hh-induced Nord expression fine tunes both the range and strength of BMP signaling in the developing Drosophila wing.

Data availability

The raw microarray data were deposited to the Gene Expression Omnibus public repository (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE180120; Gene Expression Omnibus series no. GSE180120).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Shu Yang

    Department of Anatomy and Cell Biology, George Washington University, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xuefeng Wu

    Department of Anatomy and Cell Biology, George Washington University, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Euphrosyne I Daoutidou

    Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ya Zhang

    Department of Anatomy and Cell Biology, George Washington University, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9060-3777
  5. MaryJane Shimell

    Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kun-Han Chuang

    Department of Anatomy and Cell Biology, George Washington University, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3241-8586
  7. Aidan J Peterson

    Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6801-3364
  8. Michael B O'Connor

    Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3067-5506
  9. Xiaoyan Zheng

    Department of Anatomy and Cell Biology, George Washington University, Washington, United States
    For correspondence
    xzheng@gwu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4983-5503

Funding

NIGMS (R01GM117440)

  • Xiaoyan Zheng

NIGMS (R35GM118029)

  • Michael B O'Connor

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

Reviewing Editor

  1. Erika A Bach, New York University School of Medicine, United States

Version history

  1. Received: August 25, 2021
  2. Preprint posted: September 6, 2021 (view preprint)
  3. Accepted: January 15, 2022
  4. Accepted Manuscript published: January 17, 2022 (version 1)
  5. Version of Record published: February 18, 2022 (version 2)

Copyright

© 2022, 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.

Metrics

  • 962
    Page views
  • 179
    Downloads
  • 7
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, 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. Shu Yang
  2. Xuefeng Wu
  3. Euphrosyne I Daoutidou
  4. Ya Zhang
  5. MaryJane Shimell
  6. Kun-Han Chuang
  7. Aidan J Peterson
  8. Michael B O'Connor
  9. Xiaoyan Zheng
(2022)
The NDNF-like factor Nord is a Hedgehog-induced extracellular BMP modulator that regulates Drosophila wing patterning and growth
eLife 11:e73357.
https://doi.org/10.7554/eLife.73357

Share this article

https://doi.org/10.7554/eLife.73357

Further reading

    1. Cell Biology
    Kazuki Hanaoka, Kensuke Nishikawa ... Kouichi Funato
    Research Article

    Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)–plasma membrane (PM) and ER–Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast Saccharomyces cerevisiae. In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus–vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Monica Salinas-Pena, Elena Rebollo, Albert Jordan
    Research Article

    Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone H1 variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential nuclear distribution of the somatic H1 repertoire in human cells through imaging techniques including super-resolution microscopy. H1 variants exhibit characteristic distribution patterns in both interphase and mitosis. H1.2, H1.3, and H1.5 are universally enriched at the nuclear periphery in all cell lines analyzed and co-localize with compacted DNA. H1.0 shows a less pronounced peripheral localization, with apparent variability among different cell lines. On the other hand, H1.4 and H1X are distributed throughout the nucleus, being H1X universally enriched in high-GC regions and abundant in the nucleoli. Interestingly, H1.4 and H1.0 show a more peripheral distribution in cell lines lacking H1.3 and H1.5. The differential distribution patterns of H1 suggest specific functionalities in organizing lamina-associated domains or nucleolar activity, which is further supported by a distinct response of H1X or phosphorylated H1.4 to the inhibition of ribosomal DNA transcription. Moreover, H1 variants depletion affects chromatin structure in a variant-specific manner. Concretely, H1.2 knock-down, either alone or combined, triggers a global chromatin decompaction. Overall, imaging has allowed us to distinguish H1 variants distribution beyond the segregation in two groups denoted by previous ChIP-Seq determinations. Our results support H1 variants heterogeneity and suggest that variant-specific functionality can be shared between different cell types.