Differential activation of JAK-STAT signaling reveals functional compartmentalization in Drosophila blood progenitors

  1. Diana Rodrigues
  2. Yoan Renaud
  3. K VijayRaghavan
  4. Lucas Waltzer  Is a corresponding author
  5. Maneesha S Inamdar  Is a corresponding author
  1. National Centre for Biological Sciences, Tata Institute of Fundamental Research, India
  2. GReD (Genetics, Reproduction and Development Institute), INSERM 1103, CNRS 6293, University of Clermont Auvergne, France
  3. University of Clermont Auvergne, France
  4. Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India, India

Abstract

Blood cells arise from diverse pools of stem and progenitor cells. Understanding progenitor heterogeneity is a major challenge. The Drosophila larval lymph gland is a well-studied model to understand blood progenitor maintenance and recapitulates several aspects of vertebrate hematopoiesis. However in-depth analysis has focused on the anterior lobe progenitors (AP), ignoring the posterior progenitors (PP) from the posterior lobes. Using in situ expression mapping, developmental and transcriptome analysis we reveal PP heterogeneity and identify molecular-genetic tools to study this abundant progenitor population. Functional analysis shows that PP resist differentiation upon immune challenge, in a JAK-STAT-dependent manner. Upon wasp parasitism, AP downregulate JAK-STAT signaling and form lamellocytes. In contrast, we show that PP activate STAT92E and remain undifferentiated, promoting survival. Stat92E knockdown or genetically reducing JAK-STAT signaling permits PP lamellocyte differentiation. We discuss how heterogeneity and compartmentalization allow functional segregation in response to systemic cues and could be widely applicable.

Data availability

RNA-seq data has been deposited in GEO under the accession number GSE152416.All data generated or analysed during this study are included in the manuscript and supporting files.Source data files have been provided for Figures 1, 3, 4, 5, 6, 7 and Figure 1-figure supplement- 1, 2, Figure 4-figure supplement- 1, 2, Figure 5-figure supplement- 1, 2, Figure 7-figure supplement- 1

Article and author information

Author details

  1. Diana Rodrigues

    Department of Developmental Biology and Genetics, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
    Competing interests
    No competing interests declared.
  2. Yoan Renaud

    Development, GReD (Genetics, Reproduction and Development Institute), INSERM 1103, CNRS 6293, University of Clermont Auvergne, Clermont Ferrand, France
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4036-8315
  3. K VijayRaghavan

    Department of Developmental Biology and Genetics, National Centre for Biological Sciences, Tata Institute of Fundamental Research, Bangalore, India
    Competing interests
    K VijayRaghavan, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4705-5629
  4. Lucas Waltzer

    University of Clermont Auvergne, Clermont-Ferrand, France
    For correspondence
    lucas.waltzer@uca.fr
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5361-727X
  5. Maneesha S Inamdar

    Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India, Bangalore, India
    For correspondence
    inamdar@jncasr.ac.in
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8243-2821

Funding

Indo-French Centre for the Promotion of Advanced Research

  • Maneesha S Inamdar

Science and Engineering Research Board

  • Maneesha S Inamdar

J C Bose Fellowship

  • Maneesha S Inamdar

Jawaharlal Nehru Centre for Advanced Scientific Research

  • Maneesha S Inamdar

Agence Nationale pour la Recherche and Fondation ARC

  • Lucas Waltzer

Indo-French Centre for the Promotion of Advanced Research

  • Lucas Waltzer

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

Reviewing Editor

  1. Jiwon Shim, Hanyang University, Republic of Korea

Publication history

  1. Received: July 24, 2020
  2. Accepted: February 16, 2021
  3. Accepted Manuscript published: February 17, 2021 (version 1)
  4. Version of Record published: March 1, 2021 (version 2)

Copyright

© 2021, Rodrigues 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

  • 2,209
    Page views
  • 306
    Downloads
  • 14
    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. Diana Rodrigues
  2. Yoan Renaud
  3. K VijayRaghavan
  4. Lucas Waltzer
  5. Maneesha S Inamdar
(2021)
Differential activation of JAK-STAT signaling reveals functional compartmentalization in Drosophila blood progenitors
eLife 10:e61409.
https://doi.org/10.7554/eLife.61409
  1. Further reading

Further reading

    1. Developmental Biology
    Yanling Xin, Qinghai He ... Shuyi Chen
    Research Article

    N 6-methyladenosine (m6A) is the most prevalent mRNA internal modification and has been shown to regulate the development, physiology, and pathology of various tissues. However, the functions of the m6A epitranscriptome in the visual system remain unclear. In this study, using a retina-specific conditional knockout mouse model, we show that retinas deficient in Mettl3, the core component of the m6A methyltransferase complex, exhibit structural and functional abnormalities beginning at the end of retinogenesis. Immunohistological and single-cell RNA sequencing (scRNA-seq) analyses of retinogenesis processes reveal that retinal progenitor cells (RPCs) and Müller glial cells are the two cell types primarily affected by Mettl3 deficiency. Integrative analyses of scRNA-seq and MeRIP-seq data suggest that m6A fine-tunes the transcriptomic transition from RPCs to Müller cells by promoting the degradation of RPC transcripts, the disruption of which leads to abnormalities in late retinogenesis and likely compromises the glial functions of Müller cells. Overexpression of m6A-regulated RPC transcripts in late RPCs partially recapitulates the Mettl3-deficient retinal phenotype. Collectively, our study reveals an epitranscriptomic mechanism governing progenitor-to-glial cell transition during late retinogenesis, which is essential for the homeostasis of the mature retina. The mechanism revealed in this study might also apply to other nervous systems.

    1. Developmental Biology
    2. Genetics and Genomics
    Xiaodong Li, Patrick J Gordon ... Edward M Levine
    Research Article

    An important question in organogenesis is how tissue-specific transcription factors interact with signaling pathways. In some cases, transcription factors define the context for how signaling pathways elicit tissue- or cell-specific responses, and in others, they influence signaling through transcriptional regulation of signaling components or accessory factors. We previously showed that during optic vesicle patterning, the Lim-homeodomain transcription factor Lhx2 has a contextual role by linking the Sonic Hedgehog (Shh) pathway to downstream targets without regulating the pathway itself. Here, we show that during early retinal neurogenesis in mice, Lhx2 is a multilevel regulator of Shh signaling. Specifically, Lhx2 acts cell autonomously to control the expression of pathway genes required for efficient activation and maintenance of signaling in retinal progenitor cells. The Shh co-receptors Cdon and Gas1 are candidate direct targets of Lhx2 that mediate pathway activation, whereas Lhx2 directly or indirectly promotes the expression of other pathway components important for activation and sustained signaling. We also provide genetic evidence suggesting that Lhx2 has a contextual role by linking the Shh pathway to downstream targets. Through these interactions, Lhx2 establishes the competence for Shh signaling in retinal progenitors and the context for the pathway to promote early retinal neurogenesis. The temporally distinct interactions between Lhx2 and the Shh pathway in retinal development illustrate how transcription factors and signaling pathways adapt to meet stage-dependent requirements of tissue formation.