Work

Transcription factor Maf promotes expression of repressor Zeb2 to drive microglia development in primitive hematopoiesis

Year: 2025

Type: article

Abstract: Microglia arise exclusively from yolk sac progenitors during primitive hematopoiesis, while other tissue-resident macrophages originate during transient-definitive and definitive hematopoiesis. Macrophage development requires the transcriptional repressor zinc finger E-box-binding homeobox 2 ( Zeb2 ), and those derived from definitive hematopoiesis depend on the −165 kb Zeb2 enhancer. However, microglia develop normally in Zeb2 Δ−165kb mice, indicating that primitive hematopoiesis relies on a distinct genetic program. We identified the molecular basis underlying this difference and show that all macrophages in Zeb2 Δ−165kb mice arise exclusively during primitive hematopoiesis. The transcription factors musculoaponeurotic fibrosarcoma oncogene homolog ( Maf ) and Jun were expressed by primitive hematopoietic progenitors but absent in progenitors of subsequent hematopoietic waves. Together, Maf and Jun induced Zeb2 expression independently of the −165 kb Zeb2 enhancer and restored macrophage development from adult bone marrow progenitors in Zeb2 Δ−165kb mice. Finally, Maf -deficient embryos exhibited severe ablation of primitive microglia development. These results define distinct transcriptional pathways controlling macrophage development during primitive hematopoiesis.

Source: Immunity

DOI: 10.1016/j.immuni.2025.11.022