Ikaros cooperates with Notch activation and antagonizes TGFβ signaling to promote pDC development

Jérôme Mastio; Célestine Simand; Giovanni Cova; Philippe Kastner; Susan Chan; Peggy Kirstetter

doi:10.1371/journal.pgen.1007485

Ikaros cooperates with Notch activation and antagonizes TGFβ signaling to promote pDC development

PLoS Genet. 2018 Jul 12;14(7):e1007485. doi: 10.1371/journal.pgen.1007485. eCollection 2018 Jul.

Authors

Jérôme Mastio¹, Célestine Simand¹, Giovanni Cova¹, Philippe Kastner^{1

2}, Susan Chan¹, Peggy Kirstetter¹

Affiliations

¹ Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U1258, CNRS UMR 7104, Université de Strasbourg, Illkirch, France.
² Faculté de Médecine, Université de Strasbourg, Strasbourg, France.

Abstract

Plasmacytoid and conventional dendritic cells (pDCs and cDCs) arise from monocyte and dendritic progenitors (MDPs) and common dendritic progenitors (CDPs) through gene expression changes that remain partially understood. Here we show that the Ikaros transcription factor is required for DC development at multiple stages. Ikaros cooperates with Notch pathway activation to maintain the homeostasis of MDPs and CDPs. Ikaros then antagonizes TGFβ function to promote pDC differentiation from CDPs. Strikingly, Ikaros-deficient CDPs and pDCs express a cDC-like transcriptional signature that is correlated with TGFβ activation, suggesting that Ikaros is an upstream negative regulator of the TGFβ pathway and a repressor of cDC-lineage genes in pDCs. Almost all of these phenotypes can be rescued by short-term in vitro treatment with γ-secretase inhibitors, which affects both TGFβ-dependent and -independent pathways, but is Notch-independent. We conclude that Ikaros is a crucial differentiation factor in early dendritic progenitors that is required for pDC identity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / metabolism
Animals
Bone Marrow Transplantation
Cell Differentiation / genetics*
Cell Line
Dendritic Cells / physiology*
Down-Regulation
Hematopoietic Stem Cells / physiology
Ikaros Transcription Factor / genetics
Ikaros Transcription Factor / metabolism*
Mice
Mice, Transgenic
Monocytes / physiology
Mutation
Receptors, Notch / metabolism*
Signal Transduction / genetics
Transforming Growth Factor beta / metabolism*
Up-Regulation

Substances

Receptors, Notch
Transforming Growth Factor beta
Zfpn1a1 protein, mouse
Ikaros Transcription Factor
Amyloid Precursor Protein Secretases

Grants and funding

This work was supported by grants from the Agence Nationale de la Recherche (ANR-07-MIME-018-02 to PKa), the Conférence de Coordination Inter-Régionale du Grand-Est of the Ligue contre le Cancer (CCIRGE-2014 to PKi and 0001K-2016 to SC) and institutional funds from INSERM, CNRS, University of Strasbourg and the ANR-10-LABX-0030-INRT grant. JM received pre-doctoral fellowships from the Ministry of Technology and Research and Fondation ARC; CS a master fellowship from the Fondation pour la Recherche Médicale (FRM-DEA20140630557) and GC a pre-doctoral fellowship from the IGBMC PhD programme (ANR-10-LABX-0030-INRT). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.