Lyl-1 regulates primitive macrophages and microglia development

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