During ontogeny, macrophage populations emerge in the Yolk Sac (YS) via two distinct progenitor waves, prior to hematopoietic stem cell development. Macrophage progenitors from the primitive/"early EMP" and transient-definitive/"late EMP" waves both contribute to various resident primitive macrophage populations in the developing embryonic organs. Identifying factors that modulates early stages of macrophage progenitor development may lead to a better understanding of defective function of specific resident macrophage subsets. Here we show that YS primitive macrophage progenitors express Lyl-1, a bHLH transcription factor related to SCL/Tal-1. Transcriptomic analysis of YS macrophage progenitors indicate that primitive macrophage progenitors present at embryonic day 9 are clearly distinct from those present at later stages. Disruption of Lyl-1 basic helix-loop-helix domain leads initially to an increased emergence of primitive macrophage progenitors, and later to their defective differentiation. These defects are associated with a disrupted expression of gene sets related to embryonic patterning and neurodevelopment. Lyl-1-deficiency also induce a reduced production of mature macrophages/microglia in the early brain, as well as a transient reduction of the microglia pool at midgestation and in the newborn. We thus identify Lyl-1 as a critical regulator of primitive macrophages and microglia development, which disruption may impair resident-macrophage function during organogenesis.

Agence Nationale pour la Recherche Paris France

Department of Pathology and Immunology Washington University School of Medicine St Louis MO 63110 USA

Gustave Roussy INSERM UMR1287 Université Paris Saclay Villejuif France

Laboratory of Immunobiology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Ministry of Education Key Laboratory of Model Animal for Disease study; Model Animal Research Center Medical school of Nanjing University Chemistry and Biomedicine Innovation center Nanjing University Nanjing 210093 China

PFIC lUMS AMMICa (US 23 INSERM UMS 3655 CNRS; Gustave Roussy Villejuif France

Plasseraud IP 33064 Bordeaux France

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